A veteran of Canadian stage and television productions, Fillion, then a University of Alberta student, made his US debut in the 1993 ABC TV-movie "Ordeal in the Arctic", a fact-based disaster drama filmed in the actor's hometown of Edmonton. He relocated to New York soon after, having landed the role of Joey Buchanan, the son of heroine Victoria Lord and the late Joe Riley on "One Life to Live". Fillion's character, who had been adopted by Clint Buchanan when he married Viki, was often put in uniquely precarious situations, such as a forbidden romance with the decades older Dorian, his mother's arch nemesis. This storyline and others on the program showcased not only the husky-voiced actor's leading man potential, but his humor and affability as he more than capably handled both the requisite melodramatic scenes as well as lighthearted comedy while winning fans who watched his portrayal and friends who enjoyed working by his side. For his efforts, he garnered a 1996 Daytime Emmy nomination as Outstanding Younger Leading Man.

Fillion went on to put his comedic skills to use when he was cast in the recurring role of Johnny Donnelly, the likable jukebox repairman boyfriend of Trayler Howard's Sharon on the ABC sitcom "Two Guys, a Girl and a Pizza Place". In the fall of 1999, "Two Guys and a Girl" left the pizza place behind, and Fillion joined the cast as a regular, moving in with Sharon and planning their upcoming wedding while attempting to bond with the difficult "Two Guys", scattered Berg (Ryan Reynolds) and jealous Pete (Richard Ruccolo).

Fillion made the move to features after he left "One Life to Live" and headed to Hollywood. He had a memorable cameo in Steve Spielberg's hard-hitting World War II drama "Saving Private Ryan" (1998), playing a Private James Ryan but not the one who is the focus of the search. He was next featured in the 1999 comedy "Blast From the Past" with a rare contemptible turn as Alicia Silverstone's shallow ex-boyfriend.

In 2002 Fillion returned to a regular role on primetime with Fox's series "Firefly" from "Buffy the Vampire Slayer" creator Joss Whedon. Playing Malcolm "Mal" Reynolds, the cynical, seemingly mercenary captain of the spaceship Serentity in a futuristic space opera that drew inspiration more from classic Westerns than from the typical sci-fi sources. Though the show, mishandled by Fox, managed to garner a loyal and devoted following, it was not enough to keep it on the air. However, Whedon cast Fillion in a recurring role as Caleb, the final "bad bad villain" faced by the Slayer on the final season of "Buffy" and then seemingly pulled off the impossible: the producer managed to turn his failed TV series, which had sold well on DVD, into a big-budget feature film, now rechristened "Serenity" (2005) in which all of the castmembers reunited. Fillion's performance proved to be the core of the film's human story, and he was posied to reprise the role of Mal again in future films in the franchise.