Five years after the events of the original series, 15-year old Ben Tennyson has returned to a normal, everyday life. His adventures done, Ben has taken off the Omnitrix and has grown from a young boy into a confident teenager. But the mysterious disappearance of Grandpa Max prompts him to wear the Omnitrix, as well as forcing Ben, Gwen, and a newly reformed Kevin Levin to search and locate him. While at the same time, enlisting the help of child Plumbers and repelling attacks from a new foe, the Highbreed.

Some time after the Highbreed are defeated, Ben, Gwen, and Kevin continue their adventures dealing with various alien threats. These include facing off with some villains from Ben's past such as Vilgax, Dr. Animo, Ghostfreak, Charmcaster and Vulkanus.