Smith was born in Brooklyn on January 21, 1938, the younger of two children of Anson Weston Smith, an Episcopal Sunday school Teacher, Writer, Editor, and executive vice President of the Financial World, and his wife Rosamond Small. They lived on 12th Street and 4th Avenue in the Park Slope section. His parents divorced while he was a child. To help keep him out of trouble, his father bought him a large Trans-Oceanic radio, and Smith became an avid fan of R&B music and the disc jockeys who played it, including "Jocko" Henderson of Philadelphia, New York's "Dr. Jive" (Tommy Smalls), the "Moon Dog" from Cleveland, Alan Freed, and Nashville's "John R." Richbourg, who later became his mentor. After selling encyclopedias and Fuller brushes door-to-door, Smith attended the National Academy of Broadcasting in Washington, D.C. After he graduated in 1960, he began working as "Daddy Jules" at WYOU in Newport News, Virginia. When the station format changed to "beautiful music", Smith became known as "Roger Gordon and Music in Good Taste". In 1962, he moved to country music station KCIJ/1050 in Shreveport, Louisiana, as the station manager and morning disc jockey, "Big Smith with the Records". He married Lucy "Lou" Lamb in 1961, and they had two children.

Disc jockey Alan Freed had played a role in the transformation of black rhythm and blues into rock and roll music, and originally called himself the "Moon Dog" after New York City street musician Moondog. Freed both adopted this name and used a recorded howl to give his early broadcasts a unique character. Smith's adaptation of the Moondog theme was to call himself Wolfman Jack and add his own sound effects. The character was based in part on the manner and style of bluesman Howlin' Wolf. It was at KCIJ in Shreveport, Louisiana that he first began to develop his famous alter ego Wolfman Jack. According to author Philip A. Lieberman, Smith's "Wolfman" persona "derived from Smith's love of horror films and his shenanigans as a 'wolfman' with his two young nephews. The 'Jack' was added as a part of the 'hipster' lingo of the 1950s, as in 'Take a page from my book, Jack,' or the more popular, 'Hit the road, Jack.'"

In 1963, Smith took his act to the border when the Inter-American Radio Advertising's Ramon Bosquez hired him and sent him to the studio and transmitter site of XERF-AM at Ciudad Acuña in Mexico, a station whose high-powered border blaster signal could be picked up across much of the United States. In an interview with Writer Tom Miller, Smith described the reach of the XERF signal: "We had the most powerful signal in North America. Birds dropped dead when they flew too close to the tower. A car driving from New York to L.A. would never lose the station." Most of the border stations broadcast at 250,000 watts, five times the U.S. limit, meaning that their signals were picked up all over North America, and at night as far away as Europe and the Soviet Union. It was at XERF that Smith developed his signature style (with phrases like "Who's this on the Wolfman telephone?") and widespread fame. The border stations made money by renting time to Pentecostal Preachers and psychics, and by taking 50 percent of the profit from anything sold by mail order. The Wolfman did pitches for dog food, weight-loss pills, weight-gain pills, rose bushes, and baby chicks. There was even a pill called Florex, which was supposed to enhance one's sex drive. "Some zing for your ling nuts," the Wolfman would say.

Wolfman Jack started his recording career in Minneapolis, Minnesota while working at KUXL Radio in 1965 with George Garrett. Garrett would help record the album "Boogie With The Wolfman" by Wolfman Jack & the Wolfpack on the Bread Label. The title tracks "Wolfman Boogie Pt. 1/Wolfman Boogie Pt. 2" was released as the first single and was written by Garrett and T.Caire. Garrett was also responsible for engineering, producing and assembling the band. A second single, "New Orleans" was also released.

In the early days, Wolfman Jack made sporadic public appearances, usually as a Master of Ceremonies for rock bands at local Los Angeles clubs. At each appearance he looked a little different because Smith had not decided what the Wolfman should look like. Early pictures show him with a goatee; however, sometimes he combed his straight hair forward and added dark makeup to look somewhat "ethnic". Other times he had a big afro wig and large sunglasses. The ambiguity of his race contributed to the controversy of his program. It was not until he appeared in the 1969 film, A Session with the Committee (a montage of skits by the seminal comedy troupe The Committee), that mainstream America got a good look at Wolfman Jack.

A clip of a 1970s radio advertisement featuring Wolfman Jack urging registration with the United States Selective Service (aka "the draft") is incorporated into the Depeche Mode cover of the song "Route 66". Those radio advertisements were extracted from half-hour radio programs that were distributed to radio stations across the country. His syndicated music radio series was sponsored by the United States Air Force, designed as a weekly program-length public Service infomercial to promote the benefits of joining the Air Force. The series ran from 1971 until 1977.

In 1971, the Mexican government decided that its overwhelmingly Roman Catholic citizens should not be subjected to proselytizing and banned the Pentecostal Preachers from the radio, taking away 80 percent of XERB's revenue. Smith then moved to station KDAY 1580 in Los Angeles, which could only pay him a fraction of his former XERB income. However, Smith capitalized on his fame by editing his old XERB tapes and selling them to radio stations everywhere, becoming one of the first rock and roll syndicated programs (as the tapes began to age, they were eventually also marketed to oldies stations). He also appeared on Armed Forces Radio from 1970 to 1986. At his peak, Wolfman Jack was heard on more than 2,000 radio stations in 53 countries. He was heard as far off as the Wild Coast, Transkei, on a station based there, Capital Radio 604. In a deal promoted by Don Kelley, The Wolfman was paid handsomely to join WNBC in New York in August 1973, the same month that American Graffiti premiered, and the station did a huge advertising campaign in local newspapers stating that the Wolfman would propel their ratings over those of their main competitor, WABC, which had "Cousin Brucie" (Bruce Morrow). The ads proclaimed, "Cousin Brucie's Days Are Numbered", and thousands of small tombstone-shaped paperweights were distributed that said, "Cousin Brucie is going to be buried by Wolfman Jack." After less than a year, WNBC hired Cousin Brucie, and Wolfman Jack went back to California to concentrate on his syndicated radio show, which was carried on KRLA-Pasadena (Los Angeles) from 1984-1987. He moved to Belvidere, North Carolina, in 1989, to be closer to his extended family. In the 80s, he did a brief stint at XEROK 80, another border blaster station that was leased by Dallas Investors Robert Hanna, Grady Sanders, and John Ryman. Ryman then moved Smith to Scott Ginsburg-owned Y95 in Dallas, Texas.

Wolfman Jack released two albums on the Wooden Nickel label: Wolfman Jack (1972) and Through the Ages (1973). His 1972 single "I Ain't Never Seen a White Man" hit #106 on the Billboard Singles Charts.

In 1973, he appeared in Director George Lucas's second feature film, American Graffiti, as himself. His broadcasts tie the film together, and Richard Dreyfuss's character catches a glimpse of the mysterious Wolfman in a pivotal scene. In gratitude for Wolfman Jack's participation, Lucas gave him a fraction of a "point" — the division of the profits from a film — and the extreme financial success of American Graffiti provided him with a regular income for life. He also appeared in the film's 1979 sequel, More American Graffiti, though only through voice-overs. In 1978, Wolfman Jack appeared as Bob "The Jackal" Smith in a made-for-TV movie Deadman's Curve, a film based on the musical careers of Jan Berry and Dean Torrence, aka Jan and Dean.

In July 1974, Wolfman Jack was the MC for the Ozark Music Festival at the Missouri State Fair grounds, a huge three-day rock festival with an estimated attendance of 350,000 people, making it one of the largest music events in history.

In 1975-80, Wolfman Jack hosted Halloween Haunt at Knott's Berry Farm, which transforms itself into Knott's Scary Farm each year for Halloween. It is the most successful special event of any theme park in the country, and has often sold out.

When the one surviving ship in what had originally been a pirate radio network of Radio Caroline North and Radio Caroline South sank in 1980, a search began to find a replacement. Because of the laws passed in the UK in 1967, it became necessary for the sales operation to be situated in the US. For a time, Don Kelley, Wolfman Jack's Business partner and personal manager, acted as the West Coast agent for the planned new Radio Caroline, but the deal eventually fell apart.

As a part of this process, Wolfman Jack was set to deliver the morning shows on the new station. To that end, Wolfman Jack recorded a number of programs that never aired, because the station didn't come on air according to schedule. (It eventually returned from a new ship in 1983 which remained at sea until 1990.) Today those tapes are traded among Collectors of his work.

In 1988, he was the host of "Little Darlin's Rock and Roll Palace", a rock and roll show on The Nashville Network, with two seasons recorded in Kissimee, Florida at little Darlin's Rock and Roll Palace. The third season was recorded in Nashville and Baltimore. The shows featured house band Rockin Robin backing the greatest artists of the '50s and '60s including The Coasters, Shirelles, Lou Christie, Tommy Roe, Del Shannon, and Roger McGuinn.

In 1989, he provided the narration for the US version of the arcade game DJ Boy. His voice was not used in the home version of the game due to memory limitations. In 1991, "Little Darlin's Rock and Roll Palace" in Kissimmee, Florida renamed the club as "Wolfman Jack's Rock and Roll Palace". The New Year's Eve grand opening featured, Joe Walsh, Melaine, Lester Chambers, The Impressions and Rockin Robin. Wolfman Jack played himself in an episode of Married... with Children ("Ship Happens: Part 1") that first aired in February 1995.

On July 1, 1995, Smith died from a heart attack at his house in Belvidere, North Carolina, shortly after finishing a weekly broadcast. He is buried at a family cemetery in Belvidere.

In 2012, the Estate of Wolfman Jack released a hip hop single featuring Wolfman Jack clips as the vocals.

In 2016 clips from the Wolfman Jack Radio Program were used in the Rob Zombie film 31.