- Nathan Fillion (Mal Reynolds): Fillion went on to star in the ABC series Castle and the web series The Rookie, and had recurring roles in Desperate Housewives and Community. He also provided voice work for the video games Halo and Mass Effect.
- Gina Torres (Zoe Alleyne): Torres went on to star in the USA Network series Suits, the CW series The Vampire Diaries, and the Netflix series Pearson. She also had recurring roles in Westworld and The Catch.
- Alan Tudyk (Hoban "Wash" Washburne): Tudyk went on to star in the Syfy series Resident Alien, the Amazon Video series The Tick, and the movie Ralph Breaks the Internet. He also provided voice work for the animated films Frozen, Moana, and Wreck-It Ralph.
- Morena Baccarin (Inara Serra): Baccarin went on to star in the Showtime series Homeland, the Fox series Gotham, and the Marvel Cinematic Universe films Deadpool and Deadpool 2. She also had recurring roles in The Mentalist and V.
- Adam Baldwin (Jayne Cobb): Baldwin went on to star in the TNT series The Last Ship and the History Channel series Six. He also had recurring roles in The X-Files and Chuck.
- Jewel Staite (Kaylee Frye): Staite went on to star in the Space Channel series Stargate: Atlantis and the web series The Magicians. She also had recurring roles in NCIS and The Killing.
- Ron Glass (Shepherd Book): Glass went on to have recurring roles in The West Wing, Desperate Housewives, and Castle. He also had voice roles in the animated series Justice League and The Legend of Korra.