In 2002, Fillion starred as Captain Malcolm Reynolds in the Joss Whedon science fiction television series Firefly, for which he won the "Cinescape Genre Face of the Future - Male" award by the Academy of Science Fiction, Fantasy & Horror Films, USA. Fillion also won the SyFy Genre Awards in 2006 for Best Actor/Television and was runner-up for Best Actor/Movie. Although the show was cancelled, it was adapted to the big screen; Fillion reprised his role as Mal in Whedon's movie Serenity (2005). He also had a recurring role as Caleb in the final season of Whedon's series Buffy the Vampire Slayer. Fillion considered his time on Firefly to be the most fun he had on a television series.
Fillion has lent his voice to the animated series King of the Hill in 2001, the video game Jade Empire (as the voice of Gao the Lesser), and the animated series Justice League Unlimited (as Vigilante in the episodes "Hunter's Moon" and "Patriot Act") in 2005 and 2006. Fillion starred in James Gunn's 2006 horror film Slither. For his starring role as Bill Pardy, he garnered a 2006 Fangoria Chainsaw Awards nomination in the category of Dude You Don't Wanna Mess With. Fillion starred in the romantic comedy film Waitress, written and directed by the late Adrienne Shelly, which premiered at the Sundance Film Festival January 21, 2007 and opened in theaters on May 2, 2007. According to Box Office Mojo, Waitress grossed $22,125,001 in worldwide sales as of 13 May 2008, and $29.22 million in rentals as of 28 January 2008. Fillion also starred in White Noise 2: The Light. He has made one appearance in the 2006-2007 season of the television show Lost, as Kevin, Kate's ex-husband.
In October 2006, Fillion signed a talent holding contract with the Fox Broadcasting Company, and in December 2006, The Hollywood Reporter confirmed that Fillion was cast in the lead role of Alex Tully in the series Drive, which debuted on Fox in the spring of 2007. Drive was created by Fillion's longtime friend and former Angel and Firefly writer Tim Minear. Ivan Sergei played Alex Tully in the original pilot episode of Drive. The first two Drive episodes premiered on April 13, 2007 in Canada (April 15, 2007 in the United States). However, the show did not deliver the ratings Fox desired, and on April 25, 2007, the network announced that the series was cancelled. The final two produced episodes were supposed to air back-to-back on Fox in July 2007, but did not actually become available until July 15 when they were posted on Drive's MySpace page. Fox has since removed Drive episodes from that Myspace. All six episodes are now available for download from Amazon.com and iTunes.
Fillion and actress Dana Delany joined the cast of ABC's Desperate Housewives at the beginning of the Fall 2007 season. His first appearance was in the episode "Now You Know", which aired on September 30, 2007.
Fillion plays the voice of a Marine Sergeant in the Xbox 360 game Halo 3. He is joined by his Firefly co-stars Adam Baldwin and Alan Tudyk who both voice marines. At one point early in the first mission, he identifies himself as "[Sergeant] Reynolds" over the radio, referring to his character's name from the TV series Firefly. All three actors are given personalities in the game that match those of their characters from Firefly.
The independent feature film Trucker in which Fillion plays the character Runner was premiered at the New York 2008 Tribeca Film Festival.
Filming finished on Joss Whedon's Dr. Horrible's Sing-Along Blog on 21 March 2008, which stars Nathan Fillion as Captain Hammer, Neil Patrick Harris as Dr. Horrible and Felicia Day as Penny. The teaser trailer hit the web on June 25, 2008. The episodes aired without commercials on July 15, 17 and 19, remaining available until midnight July 20. It is now airing online with commercials at Hulu, Hulu HD, Myspace. Like many TV programs they are available to download for a nominal fee from iTunes and will be available on DVD at a later date. Due to problems with the server, the episodes were also made available on iTunes earlier than planned—and promptly shot to #1 in the TV Episode download chart—and also the TV Series chart, despite only one episode having been released at the time). Dr. Horrible's Sing-Along Blog Soundtrack makes top 40 Album list despite being a digital exclusive only available on Itunes.
Fillion announced in 2008 that he had written a pilot and couple of episodes for a comedy with the working title Repo Brothers which has been picked up by ABC. Also in 2008, Fillion started working on a TV series for ABC called Castle, in which he plays Nick Castle, a mystery novelist who helps the NYPD solve crimes. In August 2008, ABC green-lit the production of the series, which will air sometime in 2009.
Nathan Fillion made EW's The Must List: What's Hot for the Week of Oct. 5, 2008.
Fillion also is featured in a spoof porn web video on Spike called "Nailing Your Wife..
He has been recognized several times for his looks including in 2007 when Fillion was featured in People magazine's Sexy Men issue under the "Domestic Bliss/Guys Worth Running Home to" section. As well, he was listed as one of Entertainment Weekly's "50 Actors We'd Watch in Anything".
Fillion recently had his pilot "Repo Brothers picked up by ABC, April 2008.