High school student Tazuna Takatsuki is a kind young fellow who is in love with mechanics, stopping anytime to help anyone fix anything problems that have to do with mechanics, and he is almost always successful. When he goes to an university to meet a scientist named Nagamasa Makihara who has requested his help in fixing something, only to come across a hospital room where a young girl with short white hair is lying unconscious on a bed. Reminded strongly of his deceased sister, Tazuna approaches the girl, only for her to wake up and reach for his hand. The moment their hands make contact, both of them are transported to an alternate reailty, where Tazuna collapses, only to wake up to find himself back in the room, with the girl awake and Makihara dancing with glee. Makihara barely explains the details clearly, only bluntly stating that Tazuna cannot let go of the girl, Koyori Akutagawa's hand or else she will die. When Tazuna looks up however, Makihara is gone, and the duo are attacked by metal chains snaking through the walls. The two escape, only to be confronted by a rebellious-looking man that controls the chains, along with a young woman treated like a puppy dog. The man roughly introduces himself as Break and the girl Bind, but makes one point clear: he has come to kill them. Tazuna and Koyori runs, but the chains are everywhere. It seems the two are doomed, when metallic gears materialize suddenly, forming a protective barrier around Koyori and Tazuna before taking the form of a sword. Together, Tazuna and Koyori stab Break as Bind reaches her limit, and wins the battle.

Makihara finally settles down sufficiently to explain that Koyori and Tazuna are now a group of Hand Shakers, two people that combine abilities to challenge God through holding hands, thus the name Hand Shakers. This act also enables them to stay in the twisted reality of Ziggurat, where other Hand Shakers battle with one another and is also the very core of their Nimrod, or power. Makihara is researching the various reasons of Hand Shakers' existence, and originally planned to keep Koyori asleep before she found her partner, lest her life force be drained. However now, with Tazuna, Koyori can live on, and Makihara takes the both of them to Tazuna's house, lying that Koyori will be staying with them as she is on an exchange program in Tazuna's school. With the price of constantly holding hands, this results in embarrassing moments in the bathroom, and many rumours spreading around school that the duo are a couple. Meanwhile, three business partners bid goodbye after a meeting, one of them being a tiny young girl that is believed to be a middle school student who is an intern, but it turns out she is the boss of a certain company known as Centeolt, with the name of Chizuru Mitsudera, accompanied by her subordinate, a tall lanky man named Hayate Azuma.

Makihara gives Koyori a check-up, and informs Tazuna that he can let go of her hand for a maximum of fifteen minutes now, and can also eat real food. While out for lunch, Chizuru and Hayate spot Koyori and Tazuna working together in the kitchen to make the appliances more effective, and Hayate takes this chance to thank Tazuna for helping to fix his car previously. Mistaking them to be a couple, Chizuru offers to take them to the restaurant run by their company for a date. The "couple" goes, and after a wonderful time, Chizuru and Hayate reveal themselves to be Hand Shakers. Fighting ensues, but Tazuna's gears prove to be ineffective against Chizuru's circular blades, known as Dagger Blades, and Hayate's sword, known as Blade Shadow. With double Nimrods and shadow clones, this pair of Hand Shakers prove to be more than a match for Tazuna and Koyori, who has no way to fight.

Tazuna lures Hayate and Chizuru to the rooftop of a temple, where their shadow clones are ineffective and Tazuna successfully traps Chizuru and injures Hayate. Winning the battle, the two groups of Hand Shakers return to Makihara's lab, where they caution Tazuna about constantly holding hands with Koyori and revealing their identity. They also explain clearly how they are transported to Ziggurat, either within a kilometre range of one another or by targeting other groups. Despite suffering bitter defeat, the duo offer to be Tazuna and Koyori's guides around the world of Ziggurat.

During a trip around the city, Koyori and Tazuna get separated, and Tazuna goes around the whole city searching for her, fearing she will die. Koyori is confronted by the friendly Riri "Lily" Hojo, the student council president of Tazuna's school. She kindly takes Koyori with her to a card tournament, where she calls Tazuna but he does not pick up. Koyori spends the rest of the afternoon with Lily and her younger brother, Masaru, a mature young boy who is also a card game champion. The siblings play a few card games with her to pass the time, while Lily makes frequent attempts to call Tazuna. Meanwhile, he meets an odd man outside Makihara's lab, who knows a lot about Hand Shakers and Makihara. Frightened, Tazuna leaves hastily, and finally picks up Lily's call. Koyori and Tazuna finally reunite, but when Lily holds Masaru's hand, the world shifts to that of Ziggurat, and the siblings reveal their true identities as Hand Shakers and their Nimrods: two decks of shuffling cards, one pink and the other blue.

The two pairs of Hand Shakers summon their Nimrods, and Lily and Masaru then disappear into thin air. This is followed by a barrage of attacks from nowhere, which Koyori recognises comes from the attack cards in the much-loved card game "Precious Memories", the game Masaru excels most at. Unable to pinpoint the attacks, Tazuna and Koyori are at a losing end as they dodge attacks barely to make their way to Lily and Masaru, who have reappeared on a skyscraper. Due to Koyori's experience with Masaru's playing, she manages to predict his attacks while Tazuna defends them with his sword, and the duo get closer. Running out of cards, Masaru bades Lily give him her retrot cards, and he converges it into one final attack, but to no avail. Despite Tazuna's injuries, Lily and Masaru are defeated.

Tazuna returns to Makihara's lab, and questions him about his identity, to which Makihara reveals the truth that he was once a Hand Shaker. With much on his mind about it, Tazuna is further forced to help with the school's festival, where Tazuna's class is setting up a booth with free snacks. Asked to approach Lily, Tazuna apologises for the incident, to which Lily bats it away, and casually offers help, but turns out is unable to. Tazuna then asks Chizuru and Hayate for help, to which Chizuru makes Koyori wear a kimono to advertise their company. Problem solved with getting ingredients, Koyori then reveals her interest in cooking and offers to help out with the booth. After a busy two days of working, Koyori prepares a special meal for Tazuna.

While shopping, Tazuna and Koyori get thrown into another Hand Shaker battle. This time, they are up against Kodama Awaza, a popular idol famed for her singing and widely recognisable through her prominent pigtails and use of proverbs. Accompanying her as her partner is her portly manager Hibiki Moriyama. As they begin to duel, Kodama gains the upper hand as her Nimrod begins to affect the world of Ziggurat directly, forcing Tazuna and Koyori to retreat as Kodama prepares to deal the final blow. In the process of escaping, Tazuna is gravely injured and brought back to Makihara's lab for recuperation and recovery. When he is finally discharged, Koyori reveals her worries of being her burden to him due to her absence of a Nimrod to Lily while crying bitterly over Tazuna.

Tazuna's condition worsens as he soon gets a high fever. In his present condition, Makihara then forbids Tazuna from leaving the house to fight. However, Tazuna storms out at the protests of his parents and takes Koyori along. Drawing Kodama and Hibiki into the Ziggurat, they once again begin to duel. Within minutes, Tazuna is at his limit. Dealing the last blow, Kodama delivers a favourite quote of hers: True strength comes from an unbreakable will. These words spark Koyori's wish to protect Tazuna as much as he had protected her, resulting in an unexpected transformation. Changing into a white-clad fairy, Koyori successfully earns her Nimrod as well as her power of speech. With both pairs of Hand Shakers on even ground, Koyori uses her keen observation skills to predict Kodama's movements just as she had done with Masaru's cards and the two win to Kodama's utmost despair.

Koyori and Tazuna are hired by Chizuru at one of Cocktail Corn's premises. During work hours, Hayate reveals his true feelings about his boss to Tazuna and Koyori, causing Chizuru to misunderstand that he loves her. At their break, Koyori and Tazuna also come across Lily and Masaru, who enlists Tazuna's help in taking care of his older sister while volunteering to teach Tazuna how to play "Precious Memories". While shopping, the two come across Kodama making a live concert on a makeshift stage. Approached by Hibiki who formally reintroduces himself, he promises that there are no hard feelings between them. Satisfied after a great day, they bump into Makihara. After being thoroughly overjoyed at Koyori's newfound ability to speak, his joy is short-lived however as they are soon approached by the menacing man Tazuna had met previously on his quest to find Koyori. Emerging with him is another girl with an uncanny resemblance to Koyori holding his hand, as Makihara grows grim with understanding.

The menacing man introduces himself as Daichi Nagaoka, an old associate and former Hand Shaker partner of Makihara. He also introduces the white-haired girl beside him as Mayumi Akutagawa, who is none other than Koyori's twin sister. Koyori's sinister past is revealed through a flashback concerning both Makihara and Nagaoka, as well as the Akutagawa professors. Like Makihara and Nagaoka, the Akutagawa professors are Hand Shaker partners and scientists striving to discover the mystery behind Hand Shakers' existence. To help in their research, they draw one another into the Ziggurat (the two parties being two pairs of Hand Shakers) and there, Mrs Akutagawa gives birth to two white-haired twin girls: Mayumi and Koyori. Being born in the Ziggurat, the twins are naturally gifted Hand Shaker powers and become partners. While the Akutagawas are ecstatic with the success of their project, this soon proves to be a curse as the twins, being children, are easy targets. This also results in them unable to lose or let go of each other hands lest they die. The Akutagawas, filled with regret, slowly but surely get infatuated with the possibly of meeting God and killing him to protect their daughters and end this battle. It is also at this time when Makihara and Nagaoka stop being Hand Shakers as their relationship worsens and they lose their will to fight together. True to their word, the Akutagawa professors depart to kill God, but have never returned. Then Koyori and Mayumi abruptly lose all their memories, powers of speech and movement, and fall into a coma. Wishing to fulfil the Akutagawas' dream, Nagaoka kidnaps Mayumi and puts her on drugs, turning her into his Hand Shaker partner and leaving Koyori and Makihara for good. Returning to the present, Tazuna, Koyori, Mayumi and Nagaoka are drawn into the Ziggurat as they prepare to do battle.

Nagaoka reveals that he had planned their battle by sending the Houjo siblings and Kodama to fight him, trying to intimidate Tazuna and Koyori. Undeterred, Tazuna summons their gears and Koyori turns into a fairy; Nagaoka changes into a flowery coat along with Mayumi. The battle ensues, and Mayumi conjures brightly-coloured cocoons that rebound around physical objects, turning anything it touches into a flowery patch of ground. Nagaoka then causes the area to explode. At first, Koyori and Tazuna try to fall back, but are caught in the explosions as many cocoons rush after them. As they flee, Tazuna asks Koyori if she feels alright fighting her older sister, to which Koyori explains that she is able to connect to everyone she comes into contact with, which means she can also do the same with Mayumi. Emotionless like the old Koyori, Mayumi attacks everything in sight as they face off with Nagaoka. A formidable opponent, he can destroy their gears and Tazuna and Koyori are at a losing end. Tazuna then realises that Mayumi cannot fight without destroying her Nimrod, and if she pushes herself too much she will disappear and die. Nagaoka does not relent, and they use Mayumi's exhaustion as an opening to attack him repeatedly. Luring him up to a skyscraper unwisely, Mayumi places all her cocoons under it and set off dozens of explosions. In a desperate attempt, Tazuna and Koyori link hands and fight as one, defeating Nagaoka. The battle is not over yet as Mayumi persists, and is revealed to be able to speak, her first words being that she will protect Nagaoka even is it means her disappearance. At that, Koyori connects with Mayumi, her former partner, and stops the disappearance. Returning to the real world, Nagaoka makes amends with Makihara. Mayumi explains her emotions occurred when she bonded with Nagaoka and like Koyori, she can connect with the people she comes into contact with. Complimenting Tazuna, Nagaoka leaves with Mayumi, who wants to eat a parfait with him. K