Homme has described himself as "very politically conservative" and "very socially liberal", considering himself a "fallen libertarian". He owns several guns, including a classic Winchester rifle, a sawed-off shotgun, and a Beretta 9 mm target pistol. He has only ever owned one car, a silver 1967 Chevrolet Camaro, which he has owned since he was 14.

Joshua Michael Homme was born in Joshua Tree, California on May 17, 1973. He grew up in an affluent family in Palm Desert, California. His paternal grandfather, Cap, moved to the area from North Dakota. Homme's surname is of Norwegian origin and is believed to come from the town of Valle. His additional ancestry includes English, French-Canadian, German, Jewish, and Swedish. The Homme family have a local street named after them in a golfing community, and Cap has a park named after him in an exclusive enclave of the Coachella Valley. In 2011, Homme discussed having to "create your own fun" as a child growing up in the desert, stating that he did not start playing music to "get girls or make money" and that he assumed that he would grow up to be "a good contractor like [his] dad".

Other acts with which Homme has collaborated include Mondo Generator, Foo Fighters, PJ Harvey, Fatso Jetson, Mark Lanegan Band, Trent Reznor, Masters of Reality, Millionaire, Wellwater Conspiracy, U.N.K.L.E., Primal Scream, Melissa Auf der Maur, Paz Lenchantin, Death from Above 1979, Earthlings?, Mastodon, Peaches, The Strokes, Local H, Biffy Clyro, and Arctic Monkeys. He also collaborated with The Prodigy's Liam Howlett for a remix of The Prodigy track "Take Me to the Hospital" in August 2009. It was re-titled "Take Me to the Hospital (Josh Homme and Liam H.'s wreckage remix)".

Homme also has ties in Idaho and has talked in the past about spending summers there, including shaping experiences such as seeing Carl Perkins perform at the Sandpoint Music Festival and buying his first electric guitar (his Ovation Ultra GP) in a Sandpoint music store. He began playing guitar at the age of nine, after his parents denied his wishes for a drum kit. He took polka lessons on guitar from ages nine to eleven, during which he supposedly did not learn of a barre chord for the first two years, nor of a pick until his third year, lending to his unique playing style. Homme joined his first band, Autocracy, in 1985, at the age of 12.

In 1987, when he was 14 years old, Homme formed a punk rock-influenced heavy metal band with schoolmates John Garcia and Brant Bjork in Palm Desert called Katzenjammer; he was the band's Guitarist. After changing their name a few times, first to Sons of Kyuss (they released an EP of the same name), they finally shortened it to Kyuss. The band garnered a cult following by the early 1990s, often driving for hours to isolated locations in the desert and plugging into generators to perform. These events, known as "generator parties", became urban legend among rock subculture. The band became both famous for their heavy, down tuned, groove oriented music, and infamous for their backstage fights with local LA bands when they traveled into town to play gigs. This soon brought the attention of Chris Goss, who became the band's mentor, helping the band sign to a label and producing them exclusively in an effort to preserve their sound. Due to Homme being younger than 18 at the time of the band's signing, his parents had to sign on his behalf. Kyuss released three major label albums, Blues for the Red Sun, Welcome to Sky Valley, and ...And the Circus Leaves Town, all of which are often cited as cornerstones to the development of the stoner rock genre in the 1990s. Kyuss partially reformed in 2010 (now known as Vista Chino), but Homme opted out of the reunion.

When Kyuss split up in 1995, Homme joined the Screaming Trees as a rhythm Guitarist, touring but not recording with the band. He and vocalist Mark Lanegan became close friends during this time. Disliking the band's continual disharmony, Homme left after just over one year with them. He founded Gamma Ray, a group more centered to his unique style and tastes, which later became Queens of the Stone Age in 1997. The first release under this name would be the Kyuss/Queens of the Stone Age compilation EP featuring tracks from both Kyuss and songs recorded from the Gamma Ray sessions. Shortly thereafter, Queens of the Stone Age released their eponymous debut album in 1998. Originally, Homme had asked a number of Singers, including Lanegan, to perform as lead vocalist for Queens of the Stone Age, but ended up singing for the first time in his career.

Homme founded The Desert Sessions in 1997 at the Rancho De La Luna in Joshua Tree, California, describing it as a musical collective series "that cannot be defined". He stated:

In 1998, Homme formed Eagles of Death Metal with friend Jesse Hughes. Recordings from this project first appeared on Homme's The Desert Sessions Volumes 3 & 4, released that year. Over the next few years, Homme became distracted from EoDM due to the success of Queens of the Stone Age. However, in an October 2008 interview, he re-affirmed his commitment to the band saying, "This isn't a side project for me. I'm in two bands. I have musical schizophrenia, and this is one of those personalities.

Homme has over 20 tattoos. On his knuckles, he has his grandparents' nicknames ("Cam" for "Camille" on the left and "Cap" on the right) with hearts and his two sons' names ("ORH" for "Orrin Ryder Homme" and "Wolf"). He has his daughter's name, also Camille, tattooed over his heart. His left arm has a switchblade with "Stay Sharp" underneath, while his inner right arm has a straight-edge razor with "Born to Win" inscribed; underneath, his nickname, "Baby Duck", is a shared tattoo with his Eagles of Death Metal bandmate Jesse Hughes, who has his nickname "Boots Electric" in the same location. Homme also shares a tattoo that says "Freitag 4:15" with former Queens of the Stone Age bandmates Nick Oliveri and Mark Lanegan and their sound Engineer Hutch, commemorating their "worst show ever" at the Rock Am Ring Festival in Germany on Friday, June 1, 2001, at 4:15 pm. They all got the tattoo on their ribs so that it would hurt the most and serve as a reminder.

Homme contributed (along with Nick Oliveri and Brad Wilk) to the Soundtrack for the 2002 film The Dangerous Lives of Altar Boys. He and Alain Johannes were originally meant to develop a score for the video game Spec Ops in 2005, however the project was cancelled (before it would become Spec Ops: The Line in 2012) and any work done on the game would go unused. Homme was also to provide music including a cover of Joe Walsh's In the City for the 2005 video game adaption of the classic film The Warriors, which also went unused.

In 2004, Homme was arrested for assaulting Dwarves frontman Blag Dahlia and Karl Doyle, at Los Angeles' Dragonfly club. Pleading no contest, Homme was ordered to remain at least 100 yards (91.44 meters) away from Dahlia and the club, was sentenced to 3 years probation with community Service, and was forced to enter a rehab program for 60 days.

On December 3, 2005, Homme married singer and musician Brody Dalle of The Distillers. They reside in Palm Springs, California with their daughter, Camille Harley Joan Homme (born January 17, 2006), and two sons, Orrin Ryder Homme (born August 12, 2011) and Wolf Dillon Reece Homme (born February 13, 2016).

Homme, along with friend and Kyuss/QOTSA contributor/producer Chris Goss, performed as "The 5:15ers" at the inaugural ArthurBall (an offshoot of the ArthurFest festival) in Los Angeles on January 26, 2006. The two were credited as "The Fififf Teeners" when they co-produced QOTSA's second album, Rated R, and 2007 album, Era Vulgaris.

Queens of the Stone Age's fifth album, Era Vulgaris, was released in early June 2007 and received generally positive reviews from critics. Following the album's touring cycle, the band took a break to focus on individual projects, during which Homme continued to produce and create more records outside the band. This break would unintentionally turn into a six-year gap between albums.

In his approach to choosing his equipment, Homme tends to look for the odd or unique, opting to stay away from the typical choices of other guitar players. In an interview about guitars in 2008, Homme claimed at the time to own close to 35 guitars, saying that only 3 of them were "really good". He declared that he purposely did not have a Fender Stratocaster or a Gibson Les Paul, but that he's always in search of intriguing, unique guitars, which are not always generally accepted as "quality" guitars, but are nevertheless great to use. He said that he tends to buy "weird, Japanese" guitars, or guitars that are already "scarred" and thus have a story.

In July 2009, it was revealed that Homme, Dave Grohl and John Paul Jones were recording together for a musical project named Them Crooked Vultures. The trio performed their first show together on August 9, 2009 in Chicago at The Metro to a crowd of approximately 1,100 ticketholders. The band has been steadily touring with live rhythm guitarist/auxiliary man Alain Johannes. Their album, Them Crooked Vultures, was released by Interscope Records in the United States on November 17, 2009, and by Sony Music internationally. They performed on Saturday Night Live as a musical guest on February 6, 2010, and at Austin City Limits on October 2, 2009. Them Crooked Vultures won the Grammy Award for Best Hard Rock Performance at the 53rd Grammy Awards on February 13, 2011.

Homme said that he "died" of asphyxiation for a short time in 2010, following unexpected complications during knee surgery. He contracted a MRSA infection, which his immune system could not fight due to stress. Doctors eventually used a defibrillator to revive him following the asphyxiation. The experience left him weakened and unable to produce music for almost two years. Following this, he was confined to his bed for three months and plunged into a deep depression, considering giving up his music career. He has said that this experience greatly contributed to the making of the Queens of the Stone Age album ...Like Clockwork. He credits Transcendental Meditation with helping him recover. In June 2016, he alluded that the story about his knee surgery may have been created by "somebody else", adding that he went "in too deep" involving drugs and sank into a depression.

In September 2012, he contributed the song "Nobody to Love" for the action-drama End of Watch.

Following a performance by QOTSA at the Jay-Z-owned Made in America Festival in 2013, Homme made comments about Jay-Z during a radio interview with CBC Radio 2's Strombo Show. He explained that his band was frisked by the event's security team prior to the performance and referred to Jay-Z's personal interaction with the band as a marketing stunt:

Homme has appeared in a number of television comedies. In December 2014, Homme made an appearance on Channel 4 sitcom Toast of London. The star of the show, Matt Berry, had been working alongside Morgana Robinson (the half-sister of Homme's wife, Brody Dalle) in the BBC sitcom House of Fools (2014–2015), in which both had prominent roles. Earlier in the year, Homme also made appearances on IFC's Comedy Bang! Bang! and Portlandia.

In July 2015, Homme began hosting a weekly hour-long show called The Alligator Hour with Joshua Homme on Apple Music's newly debuted 24-hour streaming internet radio station Beats 1. The show features a highly eclectic selection of songs personally selected by Homme, interspersed with his own (often wry) introductions of, and commentary about, the various tracks on that particular week's playlist. The Alligator Hour's musical selections typically have some sort of thematic, stream-of-consciousness-type relationship to each other.

In 2016, Homme was involved in a Verbal altercation with autograph seller Jason Leckrone, who eyewitnesses said was taunting Homme for not signing autographs. Homme began to argue with Leckrone and called him an "entitled, spoiled motherfucker". In 2017, Leckrone filed a lawsuit against Homme for assault and battery.

In December 2017, Homme was captured on video kicking the camera of Shutterstock Photographer Chelsea Lauren into her face during KROQ's 'Almost Christmas' concert in Los Angeles. After staying through the show and photographing subsequent bands, Lauren went to Cedars-Sinai Medical Center for treatment. In a statement, Homme claimed that he had been kicking over lighting equipment and was unaware that he had kicked Lauren until he was informed of it the next day. Lauren disputed this, stating that Homme had made eye contact with her before kicking her. The day after the incident, Homme issued a video response, in which he admitted to kicking Lauren and apologized to her.