He starred in a string of successful comedy films such as Old School (2003), Dodgeball: A True Underdog Story (2004), Wedding Crashers (2005), The Break-Up (2006), Fred Claus (2007), Four Christmases (2008), Couples Retreat (2009), The Dilemma (2011), The Internship (2013), and Delivery Man (2013).

He is also known for his dramatic roles playing Nick Van Owen in The Lost World: Jurassic Park (1997), and Norman Bates in Psycho (1998).

He has credited his mother as the inspiration for his career, saying, "I saw her overcome stuff, and I thought if you worked hard at something you'd give yourself a chance".

Two years later, he was cast in a lead role in a proposed revival of 77 Sunset Strip that was to air on the fledgling WB Television Network, but the project ceased development after initial testing.

Afterward, Steven Spielberg cast Vaughn as Nick Van Owen in the 1997 blockbuster The Lost World: Jurassic Park, which gave him increased exposure.

Vaughn's performance in the 2003 comedy Old School increased his popularity establishing him as a leading man in comedic films.

[13][14] In 2004, Vaughn appeared alongside Ben Stiller in the buddy cop action-comedy Starsky & Hutch and the sports comedy Dodgeball: A True Underdog Story.

[15] After this series of roles, he was dubbed one of the Hollywood "Frat Pack", alongside Will Ferrell, Ben Stiller, Jack Black, and Owen Wilson.

Also in 2005, Vaughn starred alongside Owen Wilson in Wedding Crashers, which grossed over $200 million at the U.S. box office.

Critics J.R. Jones of The Chicago Reader praised both Vaughn and Wilson on their chemistry describing them as "enormously funny" adding the film is a "rich send-ups of wedding culture".

Rosie Wash of The Guardian wrote that the film, "subverts the love-conquers-all formula of traditional rom-com to arrive at the more satisfying conclusion".

Next, he moved from comedy to drama in Sean Penn's Into the Wild, a film about the adventures of Christopher McCandless, based on the best-selling book by Jon Krakauer.

[23][24] On July 31, 2012, it was announced that Vaughn would be developing a reboot produced by CBS to the sitcom The Brady Bunch, which was taken off the air in 1974.

In 2016, he starred in the crime thriller Term Life, which featured Favreau in a supporting role and was directed by Peter Billingsley.

[28] In 2018, Vaughn co-starred alongside Mel Gibson in Dragged Across Concrete, his second collaboration with S. Craig Zahler, whom he worked with the year before on Brawl in Cell Block 99.

In 2020, he starred with Kathryn Newton in the horror-comedy film Freaky, in which they play a serial killer and a teenage girl who switch bodies.

[29] In March 2022, Vaughn, Greg Olsen, and Ryan Kalil launched a podcast network and production company named Audiorama.