In 2017, he was named an Officer of the Order of Canada for "his extensive and acclaimed body of comedic work as an actor, writer, and producer."

He made his directorial debut with the documentary Supermensch: The Legend of Shep Gordon (2013), which premiered at the Toronto International Film Festival.

He created and starred in the 2022 Netflix original series, The Pentaverate, and appeared in David O. Russell's comedy thriller Amsterdam.

Myers made many appearances, including as Wayne Campbell, on Toronto's Citytv in the early 1980s, on the alternative video show City Limits hosted by Christopher Ward; Myers also made several appearances after the launch of MuchMusic, for which City Limits was essentially the prototype.

The Wayne Campbell character was featured extensively in the 1986 summer series It's Only Rock & Roll, produced by Toronto's Insight Production Company for CBC Television.

Myers began appearing on Saturday Night Live on January 21, 1989, and eventually became the first repertory player added to the show's cast in over two years.

"He quickly became one of the show's biggest draws thanks to his talent for creating oddball characters with memorable catchphrases," according to Entertainment Weekly.

[12] In addition to "Wayne's World" and "Sprockets", Myers starred in the recurring sketches "Lothar of the Hill People", "Stuart Rankin, All Things Scottish", "Lank Thompson", "Middle-Aged Man", "Simon", "Coffee Talk with Linda Richman", "Theatre Stories", "Phillip the Hyper Hypo", and "Scottish Soccer Hooligan Weekly".

One of Myers's rare non-comedic roles came in the film 54 (1998), in which he portrayed Steve Rubell, proprietor of New York City's famous 1970s disco nightclub Studio 54.

[13][14] In June 2000, Myers was sued by Universal Pictures for US$3.8 million for backing out of a contract to make a feature film based on his SNL character Dieter.

[18] In 2008, Myers co-wrote, co-produced and starred in the poorly received The Love Guru, and in 2009 had a minor role as British general Ed Fenech in Quentin Tarantino's Inglourious Basterds.

[25] Myers is a member of the band Ming Tea along with The Bangles' guitarist and vocalist Susanna Hoffs and musician Matthew Sweet.

[27] Myers's 2013 directorial debut, Supermensch: The Legend of Shep Gordon, was selected to be screened in the Gala Presentation section at the 2013 Toronto International Film Festival.

[31] In April 2019, Variety reported that Myers will be starring in and executive producing a comedy series for Netflix, which will last for six episodes and involve him playing multiple characters.

In March 2022, author and security specialist Gavin de Becker shared that segments of The Gift of Fear Master Class had been directed by Myers.

[46] He played in the 2010 Soccer Aid for UNICEF UK football match, England vs. R.O.W (Rest of the World) and scored his penalty during a sudden-death shootout after the game ended 2–2 (June 6, 2010).

[8] In 2016, Myers published a book, Canada, a memoir interwoven with reflections on his native country's history and popular culture and Prime Minister Justin Trudeau.

[11] In June 2018, during a guest appearance on Late Night with Seth Meyers, Myers stated that Britain is a "rooting interest" for him during soccer games in part because of his parents and because he is also a citizen of the country.