Blanc was born in San Francisco, California, to Eva (née Katz), a Russian Jewish immigrant, and Frederick Blank (born in New York of Russian Jewish parents), the younger of two children. He grew up in the Western Addition neighborhood in San Francisco, and later in Portland, Oregon, where he attended Lincoln High School. Growing up, he had a fondness for voices and dialect, which he began voicing at the age of 10. He claimed that he changed the spelling of his name when he was 16, from “Blank” to “Blanc”, because a teacher told him that he would amount to nothing and be like his name, a “blank”. Blanc joined the Order of DeMolay as a young man, and was eventually inducted into its Hall of Fame. After graduating from high school in 1927, he split his time between leading an orchestra, becoming the youngest conductor in the country at the age of 19, and performing shtick in vaudeville shows around Washington, Oregon, and northern California.

Blanc began his radio career at the age of 19 in 1927, when he made his acting debut on the KGW program The Hoot Owls, where his ability to provide voices for multiple characters first attracted attention. He moved to Los Angeles in 1932, where he met Estelle Rosenbaum (1909–2003), whom he married a year later, before returning to Portland. He moved to KEX in 1933 to produce and co-host his Cobweb and Nuts show with his wife Estelle, which debuted on June 15. The program played Monday through Saturday from 11:00 pm to midnight, and by the time the show ended two years later, it appeared from 10:30 pm to 11:00 pm.

With his wife’s encouragement, Blanc returned to Los Angeles and joined Warner Bros.–owned KFWB in Hollywood in 1935. He joined The Johnny Murray Show, but the following year switched to CBS Radio and The Joe Penner Show.

In December 1936, Mel Blanc joined Leon Schlesinger Productions, which was producing theatrical cartoon shorts for Warner Bros. After sound man Treg Brown was put in charge of cartoon voices, and Carl Stalling became music director, Brown introduced Blanc to animation directors Tex Avery, Bob Clampett, Friz Freleng, and Frank Tashlin, who loved his voices. The first cartoon Blanc worked on was Picador Porky (1937) as the voice of a drunken bull. He soon after received his first starring role when he replaced Joe Dougherty as Porky Pig’s voice in Porky’s Duck Hunt, which marked the debut of Daffy Duck, also voiced by Blanc.

Radio Daily magazine wrote in 1942 that Blanc “specialize[d] in over fifty-seven voices, dialects, and intricate sound effects”, and by 1946, he was appearing on over fifteen programs in various supporting roles. His success on The Jack Benny Program led to his own radio show on the CBS Radio Network, The Mel Blanc Show, which ran from September 3, 1946, to June 24, 1947. Blanc played himself as the hapless owner of a fix-it shop, as well as his young cousin Zookie. Blanc also appeared on such other national radio programs as The Abbott and Costello Show, the Happy Postman on Burns and Allen, and as August Moon on Point Sublime. During World War II, he appeared as Private Sad Sack on various radio shows, including G.I. Journal. Blanc recorded a song titled “Big Bear Lake”.

Throughout his career, Blanc, aware of his talents, protected the rights to his voice characterizations contractually and legally. He, and later his estate, never hesitated to take civil action when those rights were violated. Voice actors at the time rarely received screen credits, but Blanc was an exception; by 1944, his contract with Warner Bros. stipulated a credit reading “Voice characterization(s) by Mel Blanc”. According to his autobiography, Blanc asked for and received this screen credit from studio boss Leon Schlesinger after he was denied a salary raise. Initially, Blanc’s screen credit was limited only to cartoons in which he voiced Bugs Bunny. This changed in March 1945 when the contract was amended to also include a screen credit for cartoons featuring Porky Pig and/or Daffy Duck. This however, excluded any shorts with the two characters made before that amendment occurred, even if they released after the fact (Book Revue and Baby Bottleneck are both examples of this). By the end of 1946, Blanc began receiving a screen credit in any subsequent Warner Bros. cartoon for which he provided voices.

Blanc was a regular on the NBC Red Network show The Jack Benny Program in various roles, including voicing Benny’s Maxwell automobile (in desperate need of a tune-up), violin teacher Professor LeBlanc, Polly the Parrot, Benny’s pet polar bear Carmichael and the train announcer. The first role came from a mishap when the recording of the automobile’s sounds failed to play on cue, prompting Blanc to take the microphone and improvise the sounds himself. The audience reacted so positively that Benny decided to dispense with the recording altogether and have Blanc continue in that role. One of Blanc’s characters from Benny’s radio (and later TV) programs was “Sy, the Little Mexican”, who spoke one word at a time. He continued to work with Benny on radio until the series ended in 1955 and followed the program into television from Benny’s 1950 debut episode through guest spots on NBC specials in the 1970s.

In 1960, after the expiration of his exclusive contract with Warner Bros., Blanc continued working for them, but also began providing voices for the TV cartoons produced by Hanna-Barbera; his roles during this time included Barney Rubble of The Flintstones and Cosmo Spacely of The Jetsons. His other voice roles for Hanna-Barbera included Dino the Dinosaur, Secret Squirrel, Speed Buggy, and Captain Caveman, as well as voices for Wally Gator and The Perils of Penelope Pitstop.

For his contributions to the radio industry, Blanc has a star on the Hollywood Walk of Fame at 6385 Hollywood Boulevard. His character Bugs Bunny also has a star on the Hollywood Walk of Fame on February 8, 1960.

On January 24, 1961, Blanc was involved in a near-fatal car accident. He was driving alone when his sports car collided head-on with a car driven by 18-year-old college student Arthur Rolston on Sunset Boulevard. Rolston suffered minor injuries, but Blanc was rushed to the UCLA Medical Center with a triple skull fracture that left him in a coma for two weeks, along with sustaining fractures to both legs and the pelvis. About two weeks after the accident, one of Blanc’s neurologists tried a different approach than just trying to address Blanc himself: address his characters. Blanc was asked, “How are you feeling today, Bugs Bunny?” After a slight pause, Blanc answered, in a weak voice, “Eh… just fine, Doc. How are you?” The doctor then asked Tweety if he was there, too. “I tawt I taw a puddy tat”, was the reply. Blanc returned home on March 17. Four days later, Blanc filed a US$500,000 lawsuit against the City of Los Angeles. His accident, one of 26 in the preceding two years at the intersection known as Dead Man’s Curve, resulted in the city funding the restructuring of curves at the location.

In 1962, Mel and his son Noel formed Blanc Communications Corporation, a media company which remains in operation. Mel and his son Noel produced over 5000 public service announcements and commercials, appearing with Kirk Douglas, Lucille Ball, Vincent Price, Phyllis Diller, Liberace, and The Who.

Blanc also originated the voice and laugh of Woody Woodpecker for the theatrical cartoons produced by Walter Lantz for Universal Pictures, but stopped voicing Woody after the character’s first three shorts when he was signed to an exclusive contract with Warner Bros. Despite this, his laugh was still used in the Woody Woodpecker cartoons until 1951, when Grace Stafford recorded a softer version, while his “Guess who!?” signature line was used in the opening titles until the end of the series and closure of Walter Lantz Productions in 1972.

Blanc began smoking cigarettes when he was nine years old. He continued his pack-a-day habit until he was diagnosed with emphysema, which pushed him to quit at age 77. On May 19, 1989, Blanc was checked into Cedars-Sinai Medical Center in Los Angeles by his family when they noticed he had a bad cough while shooting a commercial; he was originally expected to recover. Blanc’s health then took a turn for the worse and doctors found that he had advanced coronary artery disease. After nearly two months of staying at the hospital, Blanc died on July 10, 1989, at Cedars-Sinai of complications from emphysema and heart disease. He was 81 years old. He is interred in Hollywood Forever Cemetery section 13, Pinewood section, plot #149 in Hollywood. Blanc’s will stated his desire to have the inscription on his gravestone read, ” That’s all folks”, the catchphrase that was the hallmark of Blanc’s character, Porky Pig.