In Welcome to Paradise, Damon and Kai met at the Mystic Falls supermarket in the 1994 Prison World. Kai had been observing Bonnie and Damon for over four months, and seemed to know a lot about them. Damon at first threatened Kai, but when the younger man promised information, Damon gave him a chance to speak, and Kai then tried to kill him. However, before he could, Bonnie intervened and used her newly-regained magic to neutralize him long enough for Damon to knock him out and bring him to the Salvatore Boarding House, where they taped him to a chair. When he reawakened, Kai defended himself by insisting that he had no intention of killing Damon, and that he only staged it to trigger enough fear and determination to motivate Bonnie so that she could tap into her magic again.
In Black Hole Sun, Kai seemed especially interested in Damon's past, and encouraged him on more than one occasion to explain why Damon believed that their current location was meant to be his own personal hell. After spending the day together, during which Kai got immense enjoyment out of teasing Damon, Bonnie and Damon read the newspaper and learned that Kai came from a family of witches and had killed four of his siblings and seriously injured a fifth in Oregon. This forced Kai to admit that the dimension in which they were trapped was actually created as a prison where he would be doomed to spend eternity in solitude. Realizing that Kai was a sociopath who was incapable of remorse or guilt, Bonnie refused to do the spell to send them to the living world, because she didn't want to unleash Kai from his prison and allow him to hurt more people. When Kai overheard Damon suggesting that they steal the Ascendant from Kai and leave without him, Kai came in and revealed that though he didn't possess magic of his own like the rest of his family/coven, he did have the ability to siphon magic from other witches and use it as he saw fit, and he demonstrated this by grabbing Bonnie's arm, absorbing her magic, and using it against Damon in the form of a Pain Infliction spell so he couldn't intervene. Kai then gave them both a choice: they could help him, and the three of them could go home as friends, or he could take all of Bonnie's magic, kill her, and then kill Damon before leaving by himself. At a lack of options, Bonnie and Damon reluctantly agreed to help Kai get home.
In The World Has Turned and Left Me Here, Bonnie killed Kai by telekinetically throwing an ax into his chest, and Damon was initially upset by this act, as he was sure they needed Kai in order to return to the living world. However, when Bonnie determined that Kai needed Bennett blood to do the spell, Damon took advantage of Kai's death and joined Bonnie in preparing to go home without him. However, Kai, who was unable to die in the prison world as a part of his punishment, eventually awakened and stopped the spell by shooting Bonnie in the stomach with a crossbow. Damon was forced to choose between healing Bonnie with his blood, or Kai leaving the prison world without them, so he ended up getting into a fight with Kai to keep him from fulfilling his goal. Kai stabbed him in the neck with an arrow, and the two wrestled for long enough that Bonnie was able to grab the Ascendant, incapacitate Kai with her magic, and send Damon home without them, as she didn't believe she would live long enough to make it there.
In Christmas Through Your Eyes, Damon attempted to kill Kai after he left Bonnie in the prison world and tried to merge with his twin sister Jo. However, Jo stopped him and argued that she believed she could win The Merge, so they planned to keep Kai inside the anti-magic barrier where he couldn't use magic against them until she was ready to do the ceremony. Unfortunately for them, while Damon and Alaric were talking, Kai, who was chained to a tombstone in the cemetery, realized that the anti-magic spell across Mystic Falls was created by magic and used his powers to siphon all of the magic from the Travelers' spell. This resulted in the spell being lifted from the town, which allowed all of the vampires to finally return to their homes there. Unfortunately for the Mystic Falls Gang, this also resulted in Kai becoming immensely powerful, and he quickly used his newly-gained magical strength to attack Damon, along with Alaric and Elena, before fleeing.
In Woke Up With a Monster, Kai kidnapped Elena outside the boarding house and brought her to the Mystic Grill before then moving her to Mystic Falls High School. Damon and Jo, with help from Jeremy and Alaric, managed to subdue and capture Kai by shooting him through the shoulder with an arrow and were then able to rescue Elena from the high school.
In Prayer For the Dying, Damon, concerned about Liz Forbes' fate after learning that vampire blood accelerates cancer, awakened Kai from his medically-induced sleep and made a deal for his release: Kai would use his powers to remove the magic from Liz's body from the vampire blood she ingested, and in exchange, Kai would have the magical power necessary to complete the Merge ceremony with Jo, using the current celestial event occurring over the town. Kai did what he was asked and removed the magic from Liz's body. Although Kai didn't perform the Merge ceremony with Jo as he expected, he did complete it with his brother Luke, against whom he ended up winning, fulfilling his deal with Damon and giving Kai leadership of the Gemini Coven.
It appeared that after the Merge between Kai and Luke took place, Damon and Kai must have met and come to an agreement that Kai would leave town once he had the power he was seeking. This assumption is due to the fact that Damon was surprised to see Kai entering the boarding house in The Day I Tried To Live, as Damon claimed to have been informed that Kai was headed back to Portland.
In The Day I Tried To Live, Kai came to the boarding house and informed Damon and Elena that an unexpected side effect of his Merge with Luke was that, along with absorbing Luke's ability to possess magic, he also adopted several of Luke's characteristics and personality traits, including the ability to feel empathy and remorse. Damon and Elena took advantage of this new-found guilt of Kai's and used it to convince him to help them contact Bonnie in the 1994 Prison World in exchange for them delivering a letter of apology to Jo on his behalf. Damon and Elena, along with Jeremy, also intentionally made Kai feel worse about Bonnie's current situation so he would try harder to help them. When Kai's sister Liv managed to locate Kai at the boarding house to take her revenge on him for killing Luke, she seemed aggravated but not surprised when she assumed that Damon found a way to make another deal with the brother she loathed, even though the deal had actually been Elena's and Kai's idea. Later, after Liv had attacked Kai, Damon rescued him from death from suffocation by giving him his blood to heal him.
In The Downward Spiral, Damon called Kai to ask about whether it was possible that another prison world existed, as he had just learned from Bonnie that she had seen his mother when the 1994 Prison World accidentally collided with another. According to Kai, after Damon was informed that it was indeed possible, Damon responded with denial that he was telling the truth, and refused to believe that his mother could still possibly be alive. Kai then accompanied Damon to the cemetery, where he dug up his mother's coffin in order to prove to Kai and himself that the video footage Bonnie had inadvertently taken in the other prison world was of someone else. Throughout the conversation, Kai hinted that Damon's mother, Lily Salvatore, is a vampire, and reminded him that Lily's presence in the 1903 prison world supported that theory. When Damon eventually opened Lily's coffin and found, to his surprise, that it was empty, Kai affectionately patted Damon on the back and informed him that everything he knew about his mother was wrong.
Later, the two returned to the boarding house, where Kai teased Damon about not telling Stefan what they had discovered. Kai used his position as Gemini Coven leader to make a deal with Damon; if Damon could arrange to have Bonnie meet with him so he could apologize to her for everything he had done to hurt her, he would help Damon free Lily from her prison world. When Bonnie, who was unwilling to forgive Kai or even be near him after he had terrorized her while she was in his prison world, refused to meet with him, Kai pressured Damon into trying harder to get her to listen to him by telling him only a small part of Lily Salvatore's story so he would be curious to learn more. Damon, desperate to figure out the truth, brought Kai to see Bonnie at the rave where she was trying to keep an eye on the humanity-less Caroline, but Bonnie became so upset at both Damon and Kai that she threatened to melt Kai's face off if she ever saw him again. After Bonnie had returned to the dorm room, Damon tried to apologize her for involving Kai when she clearly had no interest in hearing his apology, she used her magic to stab him in the same places where Kai stabbed her to demonstrate just how much pain he had caused her, and added that there was no way to show Damon how much emotional and psychological torture he put her through, no matter how much she wished she could.
When Kai returned to the boarding house to hold up his end of their bargain, Kai seemed genuinely remorseful regarding what he had to say. Damon ordered Kai to send him to the prison world to rescue his mother, but Kai argued that Damon definitely did not want to do that. Damon attacked Kai and threatened to kill him if he didn't hold up his part of the deal, Kai insisted that he was just trying to save Damon's life and was forced to confess what he had learned by going through the Gemini Coven archives - Lily, who was turned in 1858 after she died of consumption, became a Ripper, and after she left for Europe after she had been turned, she ended traveling around the continent and killing over 3,000 people. Kai then informed him that the Gemini Coven had gotten wind of what she had been doing, and ended up tracking her down in 1903 after she arrived in the New York Harbor, presumably with the intention to reunite with Damon and Stefan. It was there that the coven created the 1903 Prison World and trapped Lily inside for eternity. Damon begged him to stop talking about what he had learned, as he was too overwhelmed to hear any more, and he moved in a way that made Kai think Damon was going to hit him. Damon then collapsed in disbelief, and Kai, seemingly feeling guilty about how distraught Damon was by what Kai had told him, stated that he would show himself out and left.
It is still unclear how Lily Salvatore and Kai's ancestors crossed paths, or were connected, as Kai either did not know enough to share it with Damon or chose not to for whatever reason.
In A Bird in a Gilded Cage, Kai and Damon, along with Elena and a reluctant Bonnie, traveled together to the 1903 Prison World in order to talk to Lily Salvatore and confirm the story they had heard about her. However, unbeknownst to Kai, Damon had betrayed Kai for the sake of Bonnie getting closure from the trauma she had suffered at his hands, and he allowed her to take revenge on Kai by stabbing him and leaving him for dead in the prison world while the Damon, Elena, Bonnie, and Lily left for the living world. After they left, Kai began stumbling around the boarding house in hopes of finding anything to help him, and ran into Lily's den of vampires, who were starving after decades of desiccation.
In I'll Wed You in the Golden Summertime, Kai and Damon meet again when he appears at Alaric and Jo's wedding, where Damon played the role as Alaric's best man.
In I'm Thinking Of You All The While, Kai links Elena and Bonnie together so that as long as Bonnie lives, Elena sleeps. Kai later taunts Damon, telling him if he kills Bonnie, Elena will hate him. Damon then kills Kai by decapitating him, ending the new hybrid life he had when Damon's mother turned him.