Irwin created a run of highly regarded stage shows that incorporated elements of clowning, often in collaboration with composer Doug Skinner. These works included The Regard of Flight (1982), Largely New York (1989), Fool Moon (1993), The Harlequin Studies (2003), and Mr. Fox: A Rumination (2004). Mr. Fox is a production that Irwin has worked on for years, a biography of 19th century clown George Washington Lafayette Fox that also has autobiographical elements.

In 1996, Irwin performed with The Cadets Drum and Bugle Corps at the 1996 Summer Olympics, in a "band on the run" sequence where he played Dr. Hubert Peterson of the fictitious Federation of United Marching Associations of America.[2]

Although Irwin is best known for his theatrical clown work, he has also been featured in a number of dramatic plays. Irwin appeared in 1988 on stage with Steve Martin and Robin Williams for a production of Waiting for Godot in the role of Lucky. Lucky's only lines consist of a famous 500-word-long monologue, an ironic element for Irwin since much of his clown-based stage work was silent. He appeared in 2002 with Sally Field in the replacement cast of The Goat or Who is Sylvia?. In 2005, he starred alongside Kathleen Turner as George in a revival of Edward Albee's Who's Afraid of Virginia Woolf?. He directed the 1998 Roundabout Theatre Company production of A Flea in Her Ear.

Irwin's first featured film role was in 1980, appearing as Ham Gravy in Robert Altman's Popeye starring Robin Williams. He has appeared in over 20 films, mainly in supporting roles. Irwin's principal film roles included My Blue Heaven, a 1990 comedy with Steve Martin and Rick Moranis, and Eight Men Out, which tells the true story of the "Black Sox" gambling scandal of 1919. Irwin tap-danced in a leading role in 1991's Stepping Out with Liza Minnelli and appeared as a mime in the Paul Mazursky film Scenes from a Mall alongside Woody Allen and Bette Midler. He appeared in film adaptations of How The Grinch Stole Christmas, The Laramie Project and A Midsummer Night's Dream. In 2006, Irwin played the solitary Mr. Leeds in M. Night Shyamalan's Lady in the Water and had a small role in 2007's Across the Universe.

His most notable television roles have been Enrico Ballati, "The Flying Man", on the television series Northern Exposure, and Mr. Noodle in the Elmo's World segment of the PBS children's show Sesame Street. He has also appeared on The Cosby Show, Saturday Night Live, 3rd Rock From The Sun, and Law & Order. Irwin was featured in the 1988 music video of "Don't Worry, Be Happy" by Bobby McFerrin (along with McFerrin and Robin Williams).

Selected for the International Clown Hall Of Fame, and was inducted August 7, 1999.

In 1989, was nominated for four Tony Awards for "Largely New York": as author of a Best Play nominee, Best Actor (Play), Best Director (Play) and, with collaborator Kimi Okada, Best Choreographer. In 1999, his show "Fool Moon" won a Special Tony Award for Live Theatrical Presentation.

Won the 2005 Tony Award for Best Actor in a Play, for his performance as George in 'Who's Afraid of Virginia Woolf?'.

• Rachel Getting Married (2008) .... Paul
• "Sesame Street" .... Mr. Noodle(14 episodes, 1998-2008)

... aka Open Sesame (New Zealand: English title: new syndication title) ... aka Sesame Street Unpaved (USA: syndication title) ... aka The New Sesame Street (USA: new syndication title) - Annual Triangle Toss (2008) TV episode .... Mr. Noodle - Sock Chaos at the Laundromat (2008) TV episode .... Mr. Noodle - The Golden Triangle of Destiny (2008) TV episode .... Mr. Noodle - Sleeping Grouchy (2007) TV episode (uncredited) .... Mr. Noodle - The Tutu Spell (2007) TV episode (uncredited) .... Mr. Noodle (9 more)

• "Law & Order .... Ellison Conway (1 episode, 2008)

... aka Law & Order Prime (USA: informal title) - Bogeyman (2008) TV episode .... Ellison Conway

• Across the Universe (2007) .... Uncle Teddy
• Raving (2007) .... Dito
• Elmo's World: What Makes You Happy?(2007) (V) .... Mr. Noodle
• Dark Matter (2007) .... Herb
• "Law & Order: Criminal Intent .... Nate Royce (1 episode, 2006)

... aka Law & Order: CI (USA: promotional abbreviation) - Masquerade (2006) TV episode .... Nate Royce

• Elmo's World: Pets!(2006) (V) .... Mr. Noodle
• Lady in the Water (2006) .... Mr. Leeds
• Elmo's World: Reach for the Sky(2006) (V) .... Mr. Noodle
• Elmo Visits the Doctor(2005) (V) .... Mr. Noodle
• The Manchurian Candidate (2004) .... Scoutmaster
• The Truth About Miranda (2004) .... Emile
• Sesame Street Presents: The Street We Live On (2004) (TV) (uncredited) .... Mr. Noodle

... aka Sesame Street: Elmo's World - The Street We Live On! (USA: DVD box title)

• Igby Goes Down(2002) .... Lt. Ernest Smith, Pershing Academy
• The Laramie Project (2002) .... Harry Woods
• "The Moth (2002) TV series
• Elmo's World: The Wild Wild West (2001) (V)
• How the Grinch Stole Christmas(2000) .... Lou Lou Who

... aka The Grinch (Australia) (UK) (USA: promotional title) ... aka Dr. Seuss' How the Grinch Stole Christmas (USA: complete title) ... aka Grinch, Der (Germany)

• A Midsummer Night's Dream(1999) .... Tom Snout

... aka Sogno di una notte di mezza estate (Italy) ... aka William Shakespeare's A Midsummer Night's Dream (USA: complete title)

• Just the Ticket (1999/I) .... Ray Charles

... aka Gary & Linda (France)

• Illuminata(1998) .... Marco

... aka Illuminata (Spain)

• "3rd Rock from the Sun .... Pickles (1 episode, 1998)

... aka 3rd Rock (USA: promotional abbreviation) ... aka Life As We Know It - Pickles and Ice Cream (1998) TV episode .... Pickles

• Silent Tongue(1994) .... Comic

... aka Gardien des esprits, Le (France)

• Water Ride (1994) .... The Man in the Gray Hat
• Sister Act 2: Back in the Habit (1993) (uncredited) .... Unnamed Brother *[[1
• "The Adventures of Pete & Pete .... The Broker (1 episode)

... aka Pete and Pete (USA: short title) - 35 Hours (????) TV episode .... The Broker

• "Tribeca .... Gene Kelly (1 episode, 1993)

- The Loft (1993) TV episode .... Gene Kelly

• Manhattan by Numbers(1993) .... Floyd
• "Great Performances .... Master of Ceremony (1 episode, 1993)

- Sondheim: A Celebration at Carnegie Hall (1993) TV episode .... Master of Ceremony

• "Northern Exposure .... Enrico Ballati, The Flying Man / ... (2 episodes, 1991-1992)

- On Your Own (1992) TV episode .... Enrico Ballati, The Flying Man - Get Real (1991) TV episode .... Enrico Bellati, the Flying Man

• The Last Mile (1992) (TV)
• Stepping Out (1991) .... Geoffrey
• Hot Shots!(1991) .... Buzz Harley
• Scenes from a Mall (1991) .... Mime
• My Blue Heaven(1990/I) (as William Irwin) .... Kirby
• The Circus (1990) (TV) .... Pierrot The Clown & Miranda's Father
• Eight Men Out(1988) .... Eddie Collins
• A New Life(1988) .... Eric
• [[ "The Cosby Show" .... Eddie Bartholomew (1 episode, 1987)

- The Show Must Go On (1987) TV episode .... Eddie Bartholomew

• The Regard of Flight(1983) (TV) .... Performer

... aka The Clown Bagatelles (USA)

• Popeye(1980) .... Ham Gravy, the Old Boyfriend