McCormack played Colonel Francis Clay Mosby in the 1-hour Western television miniseries Lonesome Dove: The Series (1994), and Lonesome Dove: The Outlaw Years (1995). He starred as the immortal Matthew McCormick in the Highlander: The Series episode "Manhunt" (1996). In 1997, he appeared in The Outer Limits in the episode "Tempests". In 1998, McCormack starred in the cult hit film Free Enterprise with William Shatner, playing a character based closely on the life of the film's co-writer Mark A. Altman. A sequel is in pre-production, and it is expected that McCormack will reprise his role as Mark.[citation needed]
McCormack's role as gay lawyer Will Truman in the NBC sitcom Will & Grace from 1998 until 2006 has brought him widespread recognition.[4] Nominated for Emmy Awards on three occasions for this role, he won the award for Outstanding Lead Actor in a Comedy in 2001.[4] During the 2001 Broadway season, McCormack briefly portrayed Prof. Harold Hill (replacing Craig Bierko) in the Susan Stroman revival of The Music Man while on hiatus from Will & Grace. In August 2002, as part of the Hollywood Bowl's Summer Concert Series, he reprised the role for a one-night only appearance in which he and other artists re-created the songs from the show. He also appeared briefly in the television series Dead Like Me. McCormack also starred in the off-Broadway play Some Girl(s) with Fran Drescher in 2006 and is the executive producer of the new Lifetime comedy, Lovespring International.

He has set up his own production company called Big Cattle Productions to develop ideas for TV. The naming of the company came out of wordplay as by shortening the word "production", you get "Big Cattle Prod".
McCormack recorded a song, "The Greatest Discovery", which was written by Elton John and Bernie Taupin in 1970, for the album Unexpected Dreams: Songs from the Stars. He also wrote and sang a song called "Living with Grace" for the 2004 soundtrack to Will & Grace with piano music provided by Barry Manilow.