He started touring the comedy club circuit almost immediately after graduating college. He appeared as one of the New Faces at the 1998 Just for Laughs in Montreal. His act was televised in 2000 in Montreal at the Théâtre Saint-Denis. Tosh's first big career break came in 2001 with a performance on the Late Show with David Letterman. Tosh followed with appearances on programs such as The Tonight Show with Jay Leno, Jimmy Kimmel Live! and Comedy Central's Premium Blend. He also hosted a local late-night comedy show in Florida called Ten and served as a spokesman in Taco Bell commercials. In 2003 he performed in his own 30-minute special on Comedy Central Presents. On June 17, 2007, Comedy Central aired his stand-up special: Daniel Tosh: Completely Serious. He also hosted an episode of Comedy Central's Live at Gotham. Tosh is also a regular guest on The Bob & Tom Show. He played a small role in the feature film The Love Guru starring Mike Myers.
Tosh's Comedy Central television show Tosh.0, which showcases Internet video clips, premiered on June 5, 2009. His mocking humor is described as "envelope pushing" and frequently features punchlines that can be construed as racist, sexist or homophobic. Tosh's explanation of his non-politically correct humor is “I’m not a misogynistic and racist person...But I do find those jokes funny, so I say them.” He made the news on July 13, 2010, for beating both Jon Stewart and Stephen Colbert in ratings to have the highest rated non-animated show on the network. Tosh.0 is averaging 2.2 million viewers beating The Daily Show by 200,000 viewers and The Colbert Report by 800,000 viewers.
Tosh has said he plans to end his career on his 38th birthday, May 29, 2013. He has said he will do this by committing suicide or retiring to the beach. He keeps a countdown clock on his website, DanielTosh.com, that gives the number of days, minutes, and seconds until his 38th birthday which is when "Daniel's Groundhog Day Ends," a reference to the Bill Murray film. Tosh has described a comic's routine life on the road as "Groundhog Day."