Hendrie's father was a salesman who came to Los Angeles in 1950 after serving in the Canadian army during World War II. When Hendrie was 12 years old, listening to radio was his escape. He was a huge fan of the Top 40 D.J. "Emperor" Bob Hudson and once rode his bike to radio station KRLA in Pasadena to meet him.

Hendrie was born and raised in Arcadia, California. In 1958 when Hendrie was five years old, his family took a road trip to visit relatives in Toronto, Canada. They listened to the radio the whole way. He knew then he wanted to work in radio one day. He was one of four children in an upper-middle-class Catholic family and an altar boy at Arcadia's Holy Angels Church.

When he was 13 years old, Hendrie's parents divorced. His father moved to Europe and married a woman who had four kids. Hendrie's family home was repossessed, forcing them to move into a small rented apartment where he slept on the couch during his high school years. After graduating, Hendrie attended Pasadena City College to earn an English degree. After one year at college, he left for Orlando, Florida, in the mid 1970s. He got a job in construction working on the build-out of Disney World.

Hendrie made a demo tape and got his first DJ job at WBJW in Winter Park, a city just outside Orlando, in 1971 at age 19. In 1978, he left WBJW to do evenings at WNOE-FM in the French Quarter of New Orleans. He would go on from there to spin records up until 1988 in Miami, San Diego, Los Angeles, Utica and Fresno.

In 1989, Phil returned to the Los Angeles area to debut as a weekend talk show host on KFI, a news/talk station.

After his show was cancelled on KFI, KVEN in Ventura, California, offered him a job in August 1990. In late September 1990, Hendrie introduced his first fictional on-air character on his radio talk show: Iraqi Raj Fahneen. The Gulf War had broken out and Fahneen vociferously defended Saddam Hussein. Thinking it was a real person on the air, listeners went ballistic. An entire cast of characters evolved, and in 18 months Hendrie took the show to major market stations in Atlanta, Minneapolis, and Miami and eventually back to Los Angeles.

In October 1996 Hendrie went back to KFI to host The Phil Hendrie Show daily. Hendrie's popularity resulted in the radio show's going national in 1999 via Premiere Radio Networks, a subsidiary of Clear Channel Communications.

For the last 14 years, Hendrie has worked as an actor and voice-over Artist. From 1999 to 2009, Hendrie voiced characters on 24 episodes of the hit animated TV series King of the Hill. He also voiced characters for three episodes of Futurama from 2000 to 2002 and played three characters on the 2009 feature-length video Futurama: Into the Wild Green Yonder.

From 2001 to 2002, Hendrie appeared in the TV series Andy Richter Controls the Universe and in Judd Apatow's TV movie North Hollywood. He played Judge McCarthy on Richard Appel's A.U.S.A. in 2003. He also starred in a TV pilot he wrote and executive produced called Phil at the Gate the same year. In 2004, Hendrie voiced the computer I.N.T.E.L.L.I.G.E.N.C.E. and the Chechen terrorist in Trey Parker's and Matt Stone's motion picture Team America: World Police and starred in Steve Levitan's animated TV pilot Phil Hendrie.

From 2006 to 2007, Hendrie had a recurring role in David Mamet's The Unit and appeared in five episodes. Other TV series included NBC's sitcom Teachers, wherein as part of an ensemble cast he played the part of school Teacher Dick Green for the full season; and The Replacements, wherein he appeared in two episodes as the mayor. He was also in the 2006 TV movie Three Strikes. In 2008, Hendrie played the New Jersey Nets coach in the comedy film Semi-Pro starring Will Ferrell. Also that year, Hendrie had parts in the TV movies Mike Birbiglia's Secret Public Journal and Giants of Radio.

On June 4, 2007, it was announced that Phil Hendrie would return to radio June 25, 2007, via national syndicator Talk Radio Network (TRN), with shows airing nationally Monday through Friday from 10 PM to 1 AM Pacific Time on 100 radio stations. The show was a straight talk show until September 14, 2009, when he welcomed back his cast of characters, bringing back his original brand of radio theater. "Radio needs alternative programming, like my show, now more than ever," said Hendrie. "Having the advantage of communicating compelling and outrageous points of view through these characters is an opportunity no other host has."

Hendrie created his website, www.PhilHendrieShow.com, in 1999 during his syndication deal with Premiere Radio Networks. In 2006, he acquired ownership of the website. On March 26, 2010, Hendrie launched his revamped website with new features like "Backstage Pass" and "Phollow Phil," where Hendrie fans gain special access to his comments, photos and pre-show videos and can interact with him and his characters. In August that same year, Hendrie launched a podcast version of his national radio show on iTunes for his Backstage Pass subscribers.

In the summer of 2011, Hendrie filmed a part for Judd Apatow's motion picture This Is 40, which was in theaters in December 2012. In 2012, he played the recurring character Joe Napoli on three episodes of New Girl. Other television work in 2012 included recurring parts on six episodes of Napoleon Dynamite and a role in an episode of ABC's Emmy Award-winning TV series Modern Family. Also out in 2012 was the film Last Call, in which Hendrie was cast as the liquor company representative, Mulvahill. In 2013, Hendrie contributed voice work for the critically acclaimed Adult Swim show Rick and Morty. In 2014, Hendrie played a fictionalized version of himself in the TV series Maron, and narrated a segment of the Comedy Central program Drunk History on the show's Hawaii episode. In 2015, Hendrie joined F is for Family to play various background characters.

In 2012, Hendrie extended his brand to Pandora with a collection of comedy bits featuring such characters as Jay Santos, Chris Norton, Bobbie Dooley, David G. Hall and Ted Bell.

In 2013, it was announced that Hendrie partnered with LEG Digital and Courtside Media's Launchpad Digital Media to increase his growing digital fan base. As part of the partnership, Hendrie also launched a weekly podcast. The Dooley podcast is available on www.TheSideShowNetwork.com, www.PhilHendrieShow.com, iTunes and PodcastOne.com. The first Dooley podcast wherein she interviewed Actress Patricia Arquette garnered more than 15,000 downloads in three days.

As of 2014, Phil Hendrie's show is an all-digital audio show available for free to anyone with internet access, accessible via his website or the smartphone application TuneIn, airing between 9AM to about 11AM Pacific time. This show is also podcast for free for five days before it is replaced by more current shows for free as well. To obtain more, fans must sign up for a backstage pass on his website.