His other film credits include Fire in the Sky (1993), Striptease (1996), Cop Land (1997), The Faculty (1998), Spy Kids (2001), Charlie's Angels: Full Throttle (2003), Ladder 49 (2004), Walk the Line (2005), Flags of Our Fathers (2006), We Are Marshall (2006), Bridge to Terabithia (2007), The Men Who Stare at Goats (2009), and Safe House (2012).

AllMovie journalist Tracie Cooper wrote that, by the conclusion of The X-Files in 2002, Patrick had developed a "solid reputation within the industry", with critics, fans and co-stars alike praising his "work ethic, personality, and consistent performances.

[4] After leaving college, Patrick worked as a house painter and continued as such until a boating accident in 1984 in Lake Erie.

Patrick first appeared in several low-budget science-fiction and action films produced by Roger Corman and shot in the Philippines by Cirio H.

[6] Patrick's first major Hollywood film was Die Hard 2, in a small part as a henchman for Colonel Stuart, before landing the role of the T-1000, the villain of James Cameron's Terminator 2: Judgment Day (1991).

[2][7] After Terminator 2, Patrick landed roles in various feature films such as Last Action Hero, Fire in the Sky (both 1993) and Striptease (1996).

His performance in Fire in the Sky led The X-Files creator Chris Carter to cast him in that series for the role of John Doggett.

Patrick made several appearances on many genre magazines, with TV Guide going so far as to label him one of the Ten Sexiest Men of Sci-Fi.

[13] Director McG, who directed Terminator Salvation, said that he wanted to reintroduce characters from the previous Terminator films: "I like the idea and the perspective for the next picture that you meet Robert Patrick the way he looks today, and he's a scientist that's working on, you know, improving cell replication so we can stay healthier and we can cure diabetes and do all these things that sound like good ideas, and to once again live as idealized expressions as ourselves.

"[14] Patrick also starred in the psychological thriller The Black Water of Echo's Pond, which was directed by Italian filmmaker Gabriel Bologna.

[15] In recent years, he has appeared in such television series as Burn Notice, NCIS and True Blood, among others.

On March 28, 2017, Patrick was cast in Amazon Video horror anthology series Lore, which is based on the award-winning and critically acclaimed podcast of the same name.

In 2021, Patrick starred in Rushed, co-produced by Lars von Trier's Zentropa Entertainment, and written by Siobhan Fallon Hogan.

[21] In August 2022, Patrick revealed for the first time that he struggled with substance abuse early on in his career and how it affected his momentum of procuring different acting roles after Terminator 2.