The events depicted are set in the Star Wars Expanded Universe about 1000 years before the prequel films. It tells the story of the Battle of Ruusan which concludes the New Sith Wars between the Sith and the Jedi. The comic books series depicts the apparent destruction of the Sith order, caused by them using a destructive Force technique called a thought bomb against the Jedi but which ends up destroying the Sith as well. It describes how and why Darth Bane, the sole Sith survivor of the Battle of Ruusan reforms the Sith order into having the one-master-one-apprentice structure that we know from the movies. All these events are seen through the eyes of three children from a backwater planet recruited into the rank of the Jedi, one of whom (Darth Zannah) becomes the first apprentice in the new Sith order.
Describing the events that lead to the construction of the monument, the Valley of the Jedi, Jedi vs. Sith links up with the Jedi Knight computer game series. By involving Darth Bane and the reformation of the Sith, it also links up with the Star Wars movies.