In the first season, the plot mainly focuses on the villain Vilgax, an evil alien warlord who wants to use the Omnitrix to conquer the galaxy. Injured at the start of the season, he sends various drones to get the Omnitrix until he is healed. After he is fully healed, he attempts to retrieve it himself, only to be stopped by Ben, Gwen and Max. Furthermore, it is hinted throughout the season that Max knows more about aliens than he lets on, culminating in the revelation that he and Vilgax had fought previously. A more subtle plotline involves Ben being forced to "grow up" and learning to use the Omnitrix responsibly, with particular emphasis on that point in the episode "Kevin 11".
The second season mostly follows a "villain of the week" format. The few plot-centric episodes focus on Kevin, a super-powered 11 year old with the power to absorb different types of energies, who meets Ben in the first season. Having inadvertently allowed Kevin to absorb the Omnitrix's ability during their first meeting, Kevin serves as an antithesis to Ben. A sociopath, Kevin eventually morphs into a hideous amalgam of Ben's original ten forms and blames Ben for it. Vilgax also returns in the finale, teaming up with Kevin in the hopes of succeeding where he failed originally. Again, he fails, and both he and Kevin are trapped in an alternate dimension, the Null Void. Another important event during this season is the destruction of Ghostfreak, one of Ben's original ten forms. Having escaped from the Omnitrix, he plans to possess Ben and use the power of the Omnitrix to begin his own legacy of conquest. However, he is defeated and destroyed by Ben.
The third season has a similar yet darker plot layout. Its few plot-centric episodes focus around aliens styled on traditional horror monsters that Ben acquires as new forms through their contact with the Omnitrix. Purple-colored lightning, caused by a teleportation device created by the Frankenstein-esque alien Doctor Vicktor, heralds their appearance. Vicktor, in turn, is loyal to Ghostfreak, who is resurrected later in the third season. He plots to shroud the earth in darkness with the use of a corrodium beam projected from a space station and expanded across the earth using a transmitter in New Mexico, thus allowing him to be at full power and rule over the planet. His attempt, however, is thwarted by Ben; he dies once more from direct exposure to the sun, but not before his DNA is re-added to the Omnitrix.
The fourth season revolves around Ben's last adventures as summer vacation ends. The few plot-centric episodes revolve around the leader of the Forever Knights organization, Forever King, and his plans to deal with the Tennysons himself. He gathers many of Ben's enemies to serve as members of his group, the "Negative 10" to both battle the Tennysons and steal a powerful energy from the Plumber base at Mount Rushmore. Ben eventually defeats the Forever King, destroying the Mount Rushmore faces in the process, though it is implied that a hologram is used to recreate the faces. Ben 10: Secret of the Omnitrix is set shortly after this point.
The series' final episode shows a possible take on Ben's return to normal life following the end of his summer vacation, and ends with the reveal of his secret powers to his father and the general public, after a final climactic battle with Vilgax. The film Ben 10: Race Against Time portrays a similar situation, the difference being that Ben fights an original character created for the film and his secret remains safe.