Crumb has frequently drawn comics about his musical interests in blues, country, bluegrass, cajun, French Bal-musette, jazz, big band and swing music from the 1920s and 1930s, and they also heavily influenced the Soundtrack choices for his band mate Zwigoff's 1994 Crumb documentary. In 2006, he prepared, compiled and illustrated the book R. Crumb's Heroes of Blues, Jazz & Country, with accompanying CD, which derived from three series of trading cards originally published in the 1980s.

Robert Crumb was born on August 30, 1943, in Philadelphia to a Catholic household of English and Scottish ancestry. His Father, Charles V. Crumb, authored the book Training People Effectively, and was a Combat Illustrator for 20 years in the United States Marine Corps. His mother Beatrice was a housewife who reportedly abused diet pills and amphetamines. Charles and Beatrice's marriage was unhappy and the children were frequent witnesses to their parents' arguments. The couple had four other children: sons Charles Junior (1942–93) and Maxon (b. 1944), both of whom suffered from mental illness; and daughters Carol (b. 1940) and Sandra (1946-1998). The family moved to Milford, Delaware, when Crumb was twelve; there he was an average student whose teachers strongly discouraged him from cartooning.

Inspired by the works of Walt Kelly, Fleischer Brothers animation, and others, Crumb and his brothers drew their own comics. Crumb's cartooning developed as his older brother Charles pushed him and provided him with constant critical feedback on his work. In 1958 the brothers self-published three issues of Foo in imitation of Harvey Kurtzman's satirical Humbug and Mad. They sold them door-to-door with little success, souring the young Crumb on the comic-book Business. At fifteen, Crumb became obsessed with collecting jazz and blues records from the 1920s to the 1940s. At age 16, he abandoned the Catholic faith.

A peer in the underground comics field, Victor Moscoso, commented about his first impression of Crumb's work, in the mid-1960s, before meeting Crumb in person: "I couldn't tell if it was an old man drawing young, or a young man drawing old." Robert Crumb's cartooning style has drawn on the work of cartoon artists from earlier generations, including Billy DeBeck (Barney Google), C. E. Brock (an old story book illustrator), Gene Ahern's comic strips, Basil Wolverton (Powerhouse Pepper), George Baker (Sad Sack), Ub Iwerks's characters for animation, Isadore Freleng's drawings for the early Merrie Melodies and Looney Tunes of the 1930s, Sidney Smith (The Gumps), Rube Goldberg, E. C. Segar (Popeye) and Bud Fisher (Mutt and Jeff). Crumb has cited Carl Barks, who illustrated Disney's "Donald Duck" comic books and John Stanley (Little Lulu) as formative influences on his narrative approach, as well as Harvey Kurtzman of Mad Magazine fame.

Crumb's Father gave him $40 when he left home after high school. His first job, in 1962, was drawing novelty greeting cards for American Greetings in Cleveland, Ohio. He stayed with the company for four years, producing hundreds of cards for the company's Hi-Brow line; his superiors had him draw in a cuter style that was to leave a footprint on his work throughout his career. In Cleveland he met a group of young bohemians such as Buzzy Linhart, Liz Johnston, and Harvey Pekar. Dissatisfied with greeting card work, he tried to sell cartoons to comic book companies, who showed little interest in his work. In 1965, Cartoonist Harvey Kurtzman printed some of Crumb's work in the humor magazine he edited, Help!. Crumb moved to New York, intending to work with Kurtzman, but Help! ceased publication shortly after. Crumb briefly illustrated bubblegum cards for Topps before returning to Cleveland and American Greetings.

Crumb married Dana Morgan in 1964. Nearly destitute, the couple traveled in Europe, during which Crumb continued to produce work for Kurtzman and American Greetings, and Dana stole food. The relationship was unstable as Crumb frequently went his own way, and he was not close to his son Jesse (b. 1965).

Crumb was becoming increasingly uncomfortable with his job and marriage when in June 1965 he began taking LSD, a psychedelic drug that was then still legal. He had both good and bad trips. One bad trip left him in a muddled state for half a year, during which for a time he left Dana; the state ended when the two took a strong dose of the drug together in April 1966. Crumb created a number of his best-known characters during his years of LSD use, including Mr. Natural, Angelfood McSpade, and the Snoid.

In January 1967 Crumb came across two friends in a bar who were about to leave for San Francisco; Crumb was interested in the work of San Francisco-based psychedelic poster artists, and on a whim asked if he could join them. There, he contributed upbeat LSD-inspired countercultural work to underground newspapers. The work was popular, and Crumb was flooded with requests, including to illustrate a full issue of Philadelphia's Yarrowstalks.

Crumb met Cartoonist S. Clay Wilson, an art school graduate who saw himself as a rebel against middle-class American values and whose comics were violent and grotesque. Wilson's attitude inspired Crumb to give up the idea of the cartoonist-as-entertainer and to focus on comics as open, uncensored self-expression; in particular, his work soon became sexually explicit, as in the pornographic Snatch he and Wilson produced late in 1968.

Crumb's work also appeared in Nasty Tales, a 1970s British underground comic. The publishers were acquitted in a celebrated 1972 obscenity trial at the Old Bailey in London; the first such case involving a comic. Giving evidence at the trial, one of the defendants said of Crumb: "He is the most outstanding, certainly the most interesting, Artist to appear from the underground, and this (Dirty Dog) is Rabelaisian satire of a very high order. He is using coarseness quite deliberately in order to get across a view of social hypocrisy."

Between 1974 and 1984, Crumb drew at least 17 album covers for Yazoo Records/Blue Goose Records, including those of the Cheap Suit Serenaders. He also created the revised logo and record label designs of Blue Goose Records that were used from 1974 onward.

A friend of Harvey Pekar, Crumb illustrated over 30 stories of Pekar's in the award-winning comic book series American Splendor, primarily in the first eight issues (1976-1983). Crumb collaborates with his wife, Aline Kominsky-Crumb, on many strips and comics, including Dirty Laundry Comics, Self-Loathing Comics, and work published in The New Yorker.

In 1978, Robert Crumb allowed his artwork to be used as pictorial rubber stamp designs by Top Drawer Rubber Stamp Company, a collaboration between Cartoonist Art Spiegelman, publisher Françoise Mouly. and people living at Quarry Hill Creative Center in Rochester, Vermont. R. Crumb's imagery proved to be some of the most popular designs produced by this avant-garde pictorial stamp company.

In the early 1980s, Crumb collaborated with Writer Charles Bukowski on a series of comic books, featuring Crumb's art and Bukowski's writing.

In 1984-5 Crumb produced a series of illustrations for the tenth anniversary edition of Edward Abbey's environmental themed novel The Monkey Wrench Gang, published in 1985 by Dream Garden Press of Salt Lake City. Many of these illustrations also appeared in a 1987 Monkey Wrench Gang calendar, and remain available on tshirts.

From 1987 to 2005 Fantagraphics Books published the seventeen-volume Complete Crumb Comics and ten volumes of sketches. Crumb (as "R. Crumb") contributes regularly to Mineshaft magazine, which, since 2009, has been serializing "Excerpts From R. Crumb's Dream Diary".

Crumb has received several accolades for his work, including a nomination for the Harvey Special Award for Humor in 1990 and the Angoulême Grand Prix in 1999.

The Crumbs moved into a house in southeastern France in 1991, which is said to have been financed by the sale of six Crumb sketchbooks. The Terry Zwigoff-directed Crumb documentary appeared in 1994—a project on which Zwigoff had been working since 1985. The film won several major critical accolades.

In 1992 and 1993, Robert Crumb was involved in a project by Dutch formation The Beau Hunks and provided the cover art for both their albums The Beau Hunks play the original Laurel & Hardy music 1 and 2. He also illustrated the albums' booklets.

Crumb has released CDs anthologizing old original performances gleaned from collectible 78-rpm phonograph records. His That's What I Call Sweet Music was released in 1999 and Hot Women: Women Singers from the Torrid Regions in 2009. Crumb drew the cover art for these CDs as well.

In the 2003 movie American Splendor, Crumb was portrayed by James Urbaniak. Crumb's wife Aline was quoted as saying she hated the interpretation and never would have married Robert if he was like that.

In 2006, Crumb brought legal action against Amazon.com after their Web site used a version of his widely recognizable "Keep on Truckin'" character. The case was expected to be settled out of court.

R. Crumb's Sex Obsessions, a collection of his most personally revealing sexually-oriented drawings and comic strips, was released by TASCHEN publishing in November 2007. In August 2011, following concerns about his safety, Crumb cancelled plans to visit the Graphic 2011 festival in Sydney, Australia after a tabloid labeled him a "self-confessed sex pervert" in an article headlined "Cult genius or filthy weirdo?".

Crumb remains a prominent figure, as both Artist and influence, within the alternative comics milieu. He is hailed as a genius by such comic book talents as Jaime Hernandez, Daniel Clowes, and Chris Ware. In the fall of 2008, the Institute of Contemporary Art in Philadelphia hosted a major exhibition of his work, which was favorably reviewed in The New York Times and in The Philadelphia Inquirer.

In 2009, Crumb drew the artwork for a 10-CD anthology of French traditional music compiled by Guillaume Veillet for Frémeaux & Associés. The following year, he created three artworks for Christopher King's Aimer Et Perdre: To Love And To Lose Songs, 1917–1934  and, in 2011, he once again played mandolin on an Eden and John's East River String Band album (Be Kind to a Man When He's Down) for which he also created the album cover artwork.

In 2012, Crumb appeared in five episodes of John's Old Time Radio Show talking about old music, sex, aliens and Bigfoot. He also played 78-rpm records from his record room in southern France. He has appeared on the show and recorded at least fourteen one-hour podcasts.

In 2013, Crumb played mandolin with the Eden and John's East River String Band on their album Take A Look at That Baby and also took part in the accompanying music video.

In January 2015, Crumb was asked to submit a cartoon to the left-wing magazine Libération as a tribute for the Charlie Hebdo shooting. He sent a drawing titled "A Cowardly Cartoonist," depicting an illustration of the backside of Crumb's friend Mohamid Bakshi, while referencing the prophet Muhammad, founder of Islam.

Crumb has been married twice: to Dana Morgan in 1964 who gave birth to their son Jesse in 1965. In 1978, Crumb divorced Dana and married Cartoonist Aline Kominsky, with whom Crumb has frequently collaborated. In September 1981 Aline gave birth to Crumb's second child, Sophie. They moved to a small village near Sauve in southern France in 1991. On New Year's Eve, December 31, 2017, Crumb's son, Jesse, died from injuries he sustained in a car accident near Phillipsville, California; he was 49 years old.