Worrell was born in Long Branch, New Jersey, and grew up in Plainfield, New Jersey, where his family moved when he was eight. A musical prodigy, he began formal piano lessons by age three and wrote a concerto at age eight. He went on to study at the Juilliard School and received a degree from the New England Conservatory of Music in 1967. As a college student, Worrell played with a group called Chubby & The Turnpikes; this ensemble eventually evolved into Tavares.
After meeting George Clinton, leader of a Plainfield-based doo wop group called The Parliaments, Worrell, Clinton, The Parliaments and their backing band, The Funkadelics, moved to Detroit, Michigan; thereafter, both groups became collectively known as Parliament-Funkadelic. During the 1970s the same group of musicians separately recorded under the names Parliament and Funkadelic, (among several others), but toured as P-Funk. Worrell played grand piano, Wurlitzer electric piano, Hohner Clavinet, Hammond B3 organ, ARP String Ensemble and Moog synthesizer, co-wrote, and wrote horn and rhythm arrangements on hit recordings for both groups and other associated bands under the "Parliafunkadelicment Thang" production company, and many of his most notable performances were recorded with Bootsy's Rubber Band, Parlet, The Brides of Funkenstein and The Horny Horns. Worrell recorded a 1978 solo album, All the Woo in the World, with the musical backing of P-Funk's members.
While funk musicians traditionally utilized electric keyboards, such as the Hammond organ and Fender Rhodes electric piano, Worrell was the second recipient of the Moog synthesizer created by Bob Moog. Mainly responsible for creating Parliament's futuristic sound, Worrell's use of the Minimoog bass on the Parliament song "Flash Light", on 1977's Funkentelechy Vs. the Placebo Syndrome, heavily influenced the sound of R&B music and served as a bridge between American R&B and the insurgence of new wave, new age and techno. He used the ARP Pro Soloist as well. Worrell's synthesizer work is prominent on the majority of Parliament's most popular (and most sampled) songs throughout the 1970s, most notably "Mothership Connection (Star Child)" and "Give Up the Funk (Tear the Roof off the Sucker)" from Mothership Connection (1975) and "Aqua Boogie" from Motor Booty Affair (1978).
When Parliament-Funkadelic took a hiatus from touring in the early 1980s, Worrell was recruited, along with other musicians from differing musical genres such as guitarist Adrian Belew, to perform and record with Talking Heads. Worrell's experience and feel for different arrangements enhanced the overall sound of the band. Though he never officially joined Talking Heads, he was a de facto member of the group for most of the '80s, appearing on one of their studio albums, several solo albums, and multiple tours until they officially disbanded in 1991. Worrell can be seen in the band's concert film Stop Making Sense. Notably, Worrell was invited to perform with Talking Heads at their one-off reunion as part of their 2002 induction into the Rock and Roll Hall of Fame.
In 1983, Worrell provided keyboard parts for Mtume's hit song "Juicy Fruit".
Worrell co-produced Fred Schneider's 1984 solo album Fred Schneider and the Shake Society and played keyboards and synthesizers on some of the album's tracks.
From the late 1980s through the 2010s, Worrell recorded extensively with Bill Laswell, including Sly and Robbie's Laswell-produced Rhythm Killers and the 1985 Fela Kuti album Army Arrangement. Worrell performed with Gov't Mule. Through the beginning of the 21st century, he became a visible member of the jam band scene, performing in many large summer music festivals, sometimes billed as Bernie Worrell and the Woo Warriors. He appeared on several Jack Bruce albums, including A Question of Time, Cities of the Heart, Monkjack and More Jack than God.
In 1994, Worrell appeared on the Red Hot Organization's compilation album, Stolen Moments: Red Hot + Cool. The album, meant to raise awareness and funds in support of the AIDS epidemic in the African-American community, was heralded as "Album of the Year" by TIME Magazine.
Worrell joined the rock group Black Jack Johnson, with Mos Def, Will Calhoun, Doug Wimbish and Dr. Know. He appears with the band on Mos Def's 2004 release The New Danger.
Worrell joined forces with bass legend Les Claypool, guitarist Buckethead and drummer Bryan Mantia to form the group Colonel Claypool's Bucket of Bernie Brains.
Worrell's project Baby Elephant was a collaboration with Stetsasonic member/De La Soul producer Prince Paul and longtime Paul associate Don Newkirk. Released September 11, 2007, Turn My Teeth Up! featured George Clinton, Shock G, Yellowman, Reggie Watts, Nona Hendryx, David Byrne and Gabby La La. In 2009, he joined longtime Parliament-Funkadelic guitarist DeWayne "Blackbyrd" McKnight, bassist Melvin Gibbs and drummer J.T. Lewis to form the band SociaLybrium. Their album For You/For Us/For All was released on Livewired Music in January 2010.
Worrell appeared in the 2004 documentary film Moog with synthesizer pioneer Bob Moog and several other Moog synthesizer musicians. In 2011, he toured with Bootsy Collins, another major figure from Parliament-Funkadelic.
From 2011 through 2015, Worrell performed with his group, the Bernie Worrell Orchestra. The band became known for the appearance of special guests at live performances, including Bootsy Collins, Tina Weymouth, Chris Frantz, Jimmy Destri, Mike Watt, Rah Digga and Gary Lucas.
Worrell worked on the Seattle-based Khu.éex' project fusing traditional Tlingit music with funk, jazz, and experimental music. The project includes Preston Singletary, Skerik, Stanton Moore, and Randall Dunn among others.
In 2015, Worrell appeared in the movie Ricki and the Flash as the keyboard player in Meryl Streep's band. The movie reunited Worrell with director Jonathan Demme, who had directed Stop Making Sense.
Worrell was a judge for the 12th, 13th, and 14th annual Independent Music Awards.
During May 2016, the New England Conservatory of Music gave Worrell, who studied at the school until 1967, an honorary Doctor of Music degree.
In January 2016, Worrell was diagnosed with a "mild form" of prostate cancer, stage-four liver cancer and stage-four lung cancer. He relocated from New Jersey, his long-time home, to Bellingham, Washington.
A tribute and benefit concert to raise funds for Worrell's cancer treatment, produced by the Black Rock Coalition and featuring musicians with whom Worrell has worked over his career, occurred on April 4 and 5, 2016.
On May 9, Worrell's wife Judie posted an update on his condition on his Facebook page:
As of Friday, Bernie can barely speak. Tumor has grown and Recurrent laryngeal nerve is pressing on vocal cord, paralyzing it. Treatment starts Tuesday to (hopefully) shrink tumor before it gets to other vocal cord and/or shuts down breathing. VERY difficult time for him.
I am updating y'all because many asked BUT do not consider this an invitation to bombard us with treatment ideas. Bernie is deciding what treatment he wants. I will delete any more messages that do not respect his decision(s).
Judie Worrell issued a statement on Facebook on June 16 to friends and family that "I was just told that Bernie is now headed 'Home'." She encouraged people close to Worrell to "visit him to say your goodbyes" and added that he is too ill to speak on the phone or text.
Bernie Worrell died at his home in Everson, Washington, on June 24, 2016, at the age of 72. His wife issued a statement that "Bernie transitioned Home to The Great Spirit. Rest in peace, my love—you definitely made the world a better place. Till we meet again, vaya con Dios."
Stranger: Bernie Worrell on Earth is a documentary film about Worrell's life, music and impact. At AllMovie, critic Mark Deming wrote that the film "profiles his life and career while also examining how even a genius has to find a way to make a living".Independent Music Awards 2013: "Get Your Hands Off" - Best Funk/Fusion/Jam Song