A reunion that was supposed to spell the arrival of peaceful times is quickly shattered when Subaru Natsuki and Emilia return to Irlam village. Witnessing the devastation left behind by the calamities known as Sin Archbishops, Subaru sinks into the depths of despair as his ability to redo proves futile. As the group makes their way to the Sanctuary in search of answers, Subaru has an unexpected encounter with the Witch of Greed—Echidna. Subjected to her untamed rhythm, he is forced to dive into the spirals of the past and future. At the same time, several mysterious threats set their sights on the Sanctuary, heralding a horrific fate for the hapless people trapped within. Everlasting contracts, past sins, and unrequited love will clash and submerge into a river of blood in the second season of Re:Zero kara Hajimeru Isekai Seikatsu. Pushed to the brink of hopelessness, how long will Subaru's resolve to save his loved ones last?

Yuusuke Yotsuya has always disliked Tokyo, but he especially hates the people who live in it. He would rather thrive in a virtual world than try to get along with those around him. At the end of one school day, he sees the popular athlete Iu Shindou talking to Kusue Hakozaki, who spends less time in school due to illness. But when he looks away from the two and back again, they have seemingly disappeared. Mere moments later, Yotsuya enters a state of free-fall, and the world begins to change around him. Dropping into a large pool of water, the first thing he sees when he comes to his senses is an assortment of enormous monsters. He soon finds out that he has been brought into a game world by Shindou and Hakozaki and that he must complete a quest within 14 days. There is one thing that separates this world from the real world: anyone who dies will be brought back to life in 30 seconds as long as one party member is alive. Tasked with numerous quests that increase in difficulty over time, Yotsuya, Shindou, and Hakozaki attempt to discover the mystery behind the perplexing game world.

After a stern yet compelling speech by Otto Suwen, Subaru Natsuki solemnly swears that he will successfully make it through this timeline and save everyone he can along the way. The first step toward achieving this goal is to help Emilia work through her past; however, that is easier said than done. Feeling as if she has been lied to by everyone around her, it will be difficult for Emilia to trust anyone, even Subaru, her self-proclaimed knight. Re:Zero kara Hajimeru Isekai Seikatsu 2nd Season Part 2 presents the culmination of Subaru's experiences with the Sanctuary and its people, along with his unwillingness to give up hope on saving them.

Once again, the Game Master's world of quests unexpectedly pulls in Yuusuke Yotsuya and the rest of this old team. Accompanied by the newest addition, Keita Torii, the team reunites with Kahabell, still unaware of their actions' impact on this world. After bidding Kahabell farewell, the team sets out on their newly appointed quest—an offering of a Jiffon Buffalo at Vaikdamnia on Jiffon Island. However, as their journey to the island commences, the team shortly finds that the quest is not as simple as it initially seemed. In fact, the island is terrorized by orcs that have made a deal with its inhabitants: instead of devouring the islanders, the orcs will be granted buffalo. With the growing shortage of buffalo, the annual Vaikdamnia festival cannot proceed. But, given the importance of the team's quest, they are left with the obvious choice—rid the island of the orcs and save the islanders.