He then served as an anchor and reporter for WMAQ-TV in Chicago and KNXT-TV (now known as KCBS-TV) in Los Angeles from 1977 until 1981 when he joined CBS.
In 2001, O'Brien had a cameo appearance in P. Diddy's Bad Boy For Life music video. In early 2003, Pat O'Brien filled in for Casey Kasem three times on Kasem's radio programs American Top 40 and American Top 20, once in January, once in February, and once in March when Kasem took vacation time. O'Brien also voice-acted in an episode of The Twilight Zone entitled Mr. Motivation. His voice is used for a doll named "Mr. Motivation."
In recent years comedians have been taking aim at O'Brien -- lampooning his nasal voice, bushy moustache, and seemingly desperate on-camera attempts appear to be "hip". O'Brien has been parodied or targeted on shows like The Simpsons, Home Movies, The Howard Stern Show, South Park, The Soup, Late Night with Conan O'Brien, Best Week Ever, The Adam Carolla Show, The Opie and Anthony Show, The Boondocks, Cheap Seats, The Showbiz Show with David Spade, and by Jimmy Fallon on Saturday Night Live. He was also the subject of a TV Funhouse cartoon by Robert Smigel.
He next was lead host of the Entertainment Tonight spin-off The Insider'' from 2004-2008.
Some of the calls are believed to have been made to Access Hollywood's Shaun Robinson, stemming largely from reports that the two were 'casually romantic' together at various venues around Los Angeles.
On May 4, 2005, O'Brien was interviewed by talk show therapist Phil McGraw, which was featured during a prime time special on CBS. He disclosed the reasons behind his alcohol and drug abuse since the 1960s, as well as his experiences during rehabilitation. O'Brien also expressed remorse for the voicemail incident and apologized for what his substance abuse did to his family. O'Brien returned to The Insider the next day, and reports from newsblues.com said that O'Brien had been signed to a new deal as host of the show.
On February 8, 2008, it was reported that O'Brien re-entered rehab and Donny Osmond would be 'filling in' as the co-host of The Insider alongside Lara Spencer. On March 5, 2008, it was reported that O'Brien had been removed from The Insider, with Osmond taking his place However, a month later O'Brien resumed his hosting duties after Osmond declined to take a permanent hosting role. On September 18, 2008, O'Brien was officially fired from The Insider for writing a controversial e-mail to co-workers which insulted Lara Spencer, his replacement as anchor.