This series was originally set in the same reality as Ultimate Spider-Man, designated as Earth-12041. Despite referencing events from previous seasons, and including minor appearances of the Avengers of Earth-12041, Mission: Breakout! appeared to take place in the continuity of the new series Marvel's Spider-Man that premiered in 2017, evidenced by the guest-appearance of that show's version of Spider-Man in "Back in the New York Groove" and "Drive My Carnage." it was later confirmed that all three seasons were set the same universe as Marvel's Spider-Man.
The newly-formed Guardians of the Galaxy find a strange artifact keyed to Peter Quill's DNA. Inside is a map leading to the Cosmic Seed, a powerful weapon capable of creating a new universe. It's up to the Guardians to find and destroy the Cosmic Seed before it can wind up in the hands of Thanos, the Collector, the Grandmaster, the resurrected Ronan, the trickster Loki, and anyone else who would abuse its power to threaten the universe. While tracking down the Cosmic Seed, the Guardians come closer into finding the truth about Peter Quill's father and heritage and uncovering a hidden conspiracy.
Following Thanos's defeat and a team up with the Avengers, the Guardians of the Galaxy get their hands on a strange sarcophagus that was found on Thanos's asteroid base that has strange abilities and later stolen by Yondu. The Guardians of the Galaxy work to find the sarcophagus while competing against Mantis and the Universal Believers. This sarcophagus later hatches into Adam Warlock where the Guardians of the Galaxy were able to get him to follow his own destiny on the right path. They also discover cover the truth of the Nova Corps secret black ops unit and meet Sam Alexander on the way, they then must stop Star-Lord's father who had take a few Nova helmets for his own purposes.
Season Three: Mission Breakout
A third season has been announced at the D23 Expo. In this season, the Guardians of the Galaxy go on the run when they are framed by Collector.