Schlamme moved from his native Houston to New York City in 1973. After serving in several low level positions for production companies, he founded his own company, Schlamme Productions, in 1980. From there, he produced campaigns for a number of musicals, including Cats. He directed the first "I Want My MTV!" advertising campaign in 1981 for Producer Buzz Potamkin, and singer/songwriter Amy Grant's 1985 music video "Find a Way" for producers Fred Seibert and Alan Goodman. Throughout the 1980s, he produced a number of specials on various entertainers including Whoopi Goldberg and Rowan Atkinson.

Schlamme made his fiction film directing debut with Miss Firecracker in 1989, and then directed the 1993 comedy film So I Married an Axe Murderer, starring Mike Myers.

Starting in the late 1990s, Schlamme served as Producer for shows such as Tracey Takes On... and has directed shows such as Ally McBeal, Boston Public, Friends, ER and Shaun Cassidy's cult favorite science fiction TV show Invasion. He is an executive Producer of the American crime drama television series Snowfall which premiered on FX in July 2017.

Schlamme's nearly decade-long collaboration in television with writer-producer Aaron Sorkin began in early 1998 when they found they shared Common creative ground on the soon to be produced Sports Night. Their successful partnership in television is one in which Sorkin focuses on writing the scripts while Schlamme executive produces and occasionally directs; they have worked together on Sports Night, The West Wing, and Studio 60 on the Sunset Strip. Schlamme will create the look of the shows, work with the other Directors, discuss the scripts with Sorkin as soon as they are turned in, make design and casting decisions, and attend the budget meetings; Sorkin tends to stick strictly to writing.

Schlamme first worked with Aaron Sorkin on his short-lived ABC comedy/drama Sports Night, for which he directed 16 of its 45 episodes. Their biggest break was in 1999, teaming up again on their hit political drama The West Wing. He directed the pilot episode and from then on served as the executive Producer until 2003. He directed 14 episodes of The West Wing in addition to serving as executive Producer. In 2003, at the end of the fourth season, Schlamme and Sorkin left the show due to internal conflicts at Warner Bros. TV not involving the NBC network, thrusting Producer John Wells into an expanded role as showrunner.

In early October 2005 a pilot script dubbed Studio 7 on the Sunset Strip for a new TV series, written by Sorkin and with Schlamme attached as Producer, started circulating around Hollywood and generating interest on the web. A week later, NBC bought from Warner Bros. TV the right to show the TV series on their network for a near-record license fee in a bidding war with CBS. The show's name was later changed to Studio 60 on the Sunset Strip.

In September 2006, the pilot for Studio 60 aired on NBC, directed by Schlamme. The pilot was critically acclaimed and had high ratings, but Studio 60 experienced a significant drop in audience by mid-season. The show was cancelled after one season.

He worked on the TV series Parenthood for NBC and the now-cancelled Pan Am for ABC. Schlamme has also directed multiple episodes of the 2014 series Manhattan.

In 2017 he was elected President of the Directors Guild of America.