Crusade is an American spin-off television series from J. Michael Straczynski's Babylon 5, airing on TNT from June 9 to September 1, 1999. It is set in 2267, five years after the events of Babylon 5, and just after the movie A Call to Arms. The Drakh have released a nanovirus plague on Earth, which will destroy all life on Earth within five years if it is not stopped. The Victory class destroyer Excalibur has been sent out to look for anything that could help the search for a cure.

Like Babylon 5, Crusade was intended to have a five-year story arc, although as Straczynski notes in the DVD commentary for A Call to Arms, it was intended to resolve the Drakh plague after a season or two and move onto other storylines. Conflicts arose, however, between the producers and executives at TNT, and production was cancelled before the first episode was broadcast.

TNT's market research had indicated that the audience for Babylon 5 did not watch other TNT programming, and likewise TNT's main audience was not watching the show, making another related program unattractive to the network's management. Straczynski believes that the network's "interference" with the production was an attempt to get out of their contract by allowing them to argue that he failed to deliver the series they wanted.

Thirteen episodes were made and broadcast by TNT, with at least four more scripted. The Sci-Fi Channel attempted to pick up the show and continue production, but was unable to find room in its budget.

In 2267, six years after the end of the Shadow War, the Drakh, a former ally of the Shadows, attempt to destroy the Earth with a leftover Shadow Planet Killer. Interstellar Alliance (ISA) president John Sheridan takes command of Excalibur and Victory and leads the EarthForce and ISA fleets to victory. During the battle, the Drakh release a viral weapon into Earth's atmosphere, infecting every living thing on the planet. In five years, the virus will become active and kill everything. The Victory is destroyed in the battle, but the Excalibur survives. Command is turned over to Captain Matthew Gideon who is given a mission: explore the galaxy to find either a cure, or an ally capable of producing one ("War Zone").

At some point between 2262 and 2267 (most likely in 2264, and just before Babylon 5: The Legend of the Rangers, which took place in 2265^{[original research?]}), a civil war broke out on Earth between the Psi Corps and a group of rogue telepaths, with mundanes (non-telepaths) caught in the middle. As a result of the war, the Psi Corps (which all telepaths had been forced by law to join) was disbanded and the laws were rewritten; telepaths were given limited rights and allowed back into society, including the military (e.g. Lt. Matheson in Crusade). Few telepaths have advanced very far because of how recent the war was and due to the common fear of telepaths. Telepaths are still banned from scanning others' thoughts without consent and are required to be "deep scanned" by powerful telepaths on a regular basis to ensure that they are not violating any laws ("The Well of Forever").

After the Earth Alliance Civil War in 2261, Earth joined the ISA. As promised by John Sheridan, Mars was granted independence since ISA laws required members to free any colony where the majority of colonists wanted independence ("Rising Star"). There is still resentment between the two sides ("Ruling from the Tomb"). Earth controls most of the information systems and resources in the Solar System and Earth-based corporations control much of the Mars economy ("Objects in Motion"). As a result, there is some hostility among Mars-born humans towards Terrans and many in EarthForce do not feel obligated to risk their lives to help Earth fight the plague.

The galaxy is dealing with the Shadow technology legacy, which, among other things, includes the release of the plague on Earth by the Drakh, which is made out of Shadow technology, and Earthforce's use of it, which Gideon had to experience tragically ten years before.