A native of New York City, Smigel first established himself as a writer on Saturday Night Live by joining the writing staff when Lorne Michaels returned as executive producer for the 1985-1986 season. After the 1985-1986 season proved to be a disappointment with critics, in the ratings, and with Brandon Tartikoff (who was planning to have SNL cancelled by the last episode of season 11 due to its sliding ratings (see note on , scroll down to read), Lorne fired most of the castmembers and writers, retained the castmembers and writers who were standouts during the otherwise dismal season (Smigel being one of them), and hired new ones for the 1986-1987 season. This is when Smigel began to write more memorable sketches, including one where host William Shatner urged worshipful attendees at a Star Trek convention to "get a life." Smigel rarely appeared on screen, although he was credited as a feature player in the early 1990s and has played a recurring character in the Bill Swerski's Superfans sketches.

While on a writers' strike from Saturday Night Live following the 1987–88 season, Smigel wrote for an improvisational comedy revue in Chicago with fellow SNL writers Bob Odenkirk and Conan O'Brien called Happy Happy Good Show.

Smigel later became the first head writer at Late Night with Conan O'Brien, where he created numerous successful comedy bits, including one where Smigel performed only the lips of public figures which were superimposed on photos of the actual people. (This technique was pioneered on the Clutch Cargo cartoon series as a cost-saving measure, and was known as Syncro-Vox.)

Smigel's most famous creation, however, is the foul-mouthed puppet Triumph, the Insult Comic Dog, who mercilessly mocks celebrities and others in the style of a Borscht Belt comedian. Smigel also wrote and performed on the short-lived Dana Carvey Show.

Smigel continued to establish himself on Saturday Night Live by producing infamous, provocative, short animated segments under the title TV Funhouse, which usually satirizes public figures and popular culture. It spawned a TV show on Comedy Central featuring a mix of puppets, animation, and short sketches. Although only eight episodes were aired (during the winter of 2000 - 2001) Smigel continues to create TV Funhouse segments for Saturday Night Live and occasionally appears in films (usually alongside SNL veterans such as Adam Sandler).

Smigel's father is Irwin Smigel, DDS, "The Father of Cosmetic Dentistry," and the founder and president of the American Society for Dental Aesthetics.

For a time, Robert attempted to follow in his father's footsteps and studied dentistry at Cornell University and New York University; in the Adam Sandler feature film Punch-Drunk Love (2002), Robert Smigel actually played a dentist. He has recently written, along with Adam Sandler, "You Don't Mess with the Zohan" set for release in 2008.