In spite of the Diablo 4 Goldmajority of inhabitants of Tristram departing when a growing number of terrifying creatures began to swarm the village in the night, Cain stood steadfast and opted to stay. In the first Diablo game played by players, they were able to become the control of a character who was simply referred to as "the hero", who Blizzard was later, with Diablo 3 retconned as Prince Aidan. Cain as well as the few people who were left were able to assist the Prince and his companions by providing advice and identifying objects for a small cost. The Prince was able to defeat Diablo and thwarted his return, by driving the soulstone that contained Diablo inside Aidan's head in an attempt to contain the Lord of Terror inside Aidan's body.

Through the four acts in Diablo 2. Diablo rapidly alters the character of Prince Aidan and the prince begins to lose control over the Lord of Terror's soul , and subsequently, the release of Hell's demons yet again onto Tristram. The player, a nameless warrior, saves Cain in the process, and from then on Cain is the hero's constant companion offering to identify magical items at no cost, and also offer tips from his vast collection of old wisdom to once again defeat the monster Diablo.

Cain is back on Diablo 3 as a supporting character. The character in Diablo 3. known by the name of Nephalem regardless of which Diablo 3 class they choose Cain is asked by his Ward Leah to rescue the scholar from the ruins of Tristram Cathedral which had been struck by a "fallen star.' The three discover that the "fallen star" is actually a person who they refer to as 'the Stranger who is without memory, aside from the fact that they lost his sword. The Nephalem recuperates the sword, which was broken into three pieces, but their efforts were blocked by the cheap Diablo 4 Goldwitch Maghda , who grabs the sword's shards and captures Cain.