In the 2006 sequel Clerks II, Smith revisited the Dante and Randal characters from his first film in his final visit to the View Askewniverse. Roundly criticized before its release, the film won favorable reviews as well as two awards (the Audience Award at the Edinburgh Film Festival and the Orbit Dirtiest Mouth Award at the MTV Movie Awards). It marked Smith's third trip to the Cannes International Film Festival, where it received an eight-minute standing ovation. The $5 million film, starring Jeff Anderson, Brian O'Halloran, Rosario Dawson, Mewes, Jennifer Schwalbach and Smith reprising his role as Silent Bob, earned $25 million.
Zack and Miri Make a Porno was originally announced in March 2006 as Smith's second non-Askewniverse film. The film began shooting on January 18, 2008, in Monroeville, Pennsylvania, and wrapped on March 15, 2008. It stars Seth Rogen and Elizabeth Banks as the title characters who decide to make a low-budget pornographic film to solve their money problems. It was released on October 31, 2008, and ran into many conflicts getting an "R" rating. Rogen said:
Smith played the role of Paul, a cynical divorced man, in a Showtime television series pilot, "Manchild", filmed in December 2006. It was not picked up by the network.
In 2006 Smith appeared in a number of films, co-starring as Sam in Catch and Release, starring Jennifer Garner, and appearing as The Warlock, a hacker, in the fourth installment of the Die Hard franchise, Live Free or Die Hard. At year's end, he appeared briefly in friend and fellow writer-director Richard Kelly's Southland Tales, in which he played the legless conspiracy theorist General Simon Theory. The same year, Smith did voicework for the CGI film TMNT as a diner chef and was seen as Rusty (a friend of lead Jason Mewes) in Bottoms Up with co-star Paris Hilton.
Smith appeared in the 2006 mtvU show Sucks Less with Kevin Smith. The show gives college students ideas for things to do on the weekends.
In 2006, Smith guest reviewed on Ebert & Roeper, in place of Roger Ebert, who was recovering from thyroid cancer treatment. These spots were notable for the arguments between Smith and Richard Roeper over certain films, with Smith often citing Roeper's negative review of Jersey Girl to discredit his review of the film at hand. On one appearance, Smith compared Craig Brewer's Black Snake Moan to the works of William Faulkner.