He had already portrayed Malcolm Reynolds in Firefly and would go on to reprise the role in the film Serenity. He also starred and sang in Joss Whedon's 2008 Internet musical "Dr. Horrible's Sing-Along Blog", along side Felicia Day. Although the two both appeared in the same episodes, neither appeared on screen together.
From 2009 to 2016, he played the title role on the ABC drama Castle. On October 2017, Fillion will portrayed as John Nolan in ABC's upcoming Crime-comedy-drama series The Rookie.
He was also named in the "People's Sexiest Men Alive" 2010 magazine.
He is currently working with Alan Tudyk on a web series called Con Man, loosely based on their experiences on the convention circuit after Firefly.