He was born George Leslie Goebel in Chicago, Illinois, in 1919. His father, Hermann Goebel, who was then working as a butcher and grocer, had emigrated to the United States in the 1890s with his parents from the Austrian Empire. His mother, Lillian (MacDonald) Goebel, was a native of Illinois, as was her mother, while Lillian's father had immigrated from Scotland.

Following his graduation from Theodore Roosevelt High School in Chicago in 1937, Gobel initially pursued an entertainment career as a country music singer, performing on the National Barn Dance on WLS radio and later on KMOX in St. Louis. During World War II, he enlisted in the United States Army Air Forces and served as a FLIGHT instructor in AT-9 aircraft at Altus, Oklahoma, and later in B-26 Marauder bombers at Frederick, Oklahoma. He resumed his career as an entertainer after the war, although he decided to focus predominantly on comedy rather than just singing. Much later, in a 1969 appearance on The Tonight Show Starring Johnny Carson, Gobel joked about his stateside wartime service: "There was not one Japanese aircraft that got past Tulsa."

Gobel labeled himself "Lonesome George," and the nickname stuck for the rest of his career. The TV show typically included a segment in which Gobel appeared with a guitar, started to sing, then got sidetracked into a story, with the song always left unfinished after fitful starts and stops, a comedy approach that prefigured the Smothers Brothers. He had a special version of the Gibson L-5 archtop guitar constructed featuring diminished dimensions of neck scale and body depth, befitting his own smaller stature. Several dozen of this "L-5CT" or "George Gobel" model were produced in the late 1950s and early 1960s. He also played the harmonica.

When ratings soared on The George Gobel Show (rated in the top ten of 1954-55), Paramount promoted Gobel as their new comedy star, casting him as the lead in The Birds and the Bees (1956), a remake of The Lady Eve (1941) featuring David Niven playing a third-billed supporting role under Gobel and leading lady Mitzi Gaynor.

However, Gobel's TV success did not translate to the big screen. The film performed so poorly at the box office that release was delayed on his second movie, I Married a Woman, filmed in 1956 by RKO Radio but not released until 1958. Although scripted by Goodman Ace, it also resulted in disappointing ticket sales, and Gobel's career as a Paramount movie star came to an abrupt end. He settled into a succession of TV guest star appearances and did not return to movie screens until two decades later, as a character actor in Joan Rivers' Rabbit Test (1978), followed by The Day It Came to Earth (1979) and Ellie (1984). He appeared in nine TV movies during the 1970s and 1980s.

Interestingly, Gobel had employed the tuxedo joke at least once before, on the June 22, 1957 episode of his show. The Comedian complained that the TV Director and crew treated him: "...as if they were a tuxedo and I was a pair of brown shoes." On this occasion, the gag received a respectable, but not overwhelming, response.

From 1958 to 1961, Gobel appeared in Las Vegas at the El Rancho Vegas and in Reno at the Mapes Hotel. In 1961, Gobel starred (with Sam Levene, Barbara Nichols, and Paula Stewart) in a Broadway musical called Let It Ride!, with a score by Jay Livingston and Ray Evans. Gobel's singing voice proved accurate and charming in a laid-back manner. Critics compared the show unfavorably to How to Succeed in Business ... and it closed after only a couple of months in New York. He continued to work club dates and performed in many of the Playboy Club properties.

Gobel was a guest on various TV programs, including The Dean Martin Show; The Ford Show, Starring Tennessee Ernie Ford; The Bing Crosby Show; The Dinah Shore Show; Death Valley Days; and Johnny Carson's The Tonight Show. An episode of My Three Sons starring Fred MacMurray in December, 1960 was titled "Lonesome George", in which Gobel played himself on the episode. He appeared on F Troop as Henry Terkel in the 1966 episode: "Go for Broke."

In an often-replayed segment from a 1969 episode of The Tonight Show, Gobel followed Bob Hope and Dean Martin, walking onstage with a plastic cup with an unidentified drink. Gobel ribbed Carson about coming on last and having to follow major stars Hope and Martin. He quipped to Carson, "Did you ever get the feeling that the world was a tuxedo and you were a pair of brown shoes?", to which Carson, Hope, Martin, and the audience came unglued with laughter. After the laughter died down, Carson asked Gobel about his career in World War II as a fighter pilot. Gobel feigned bewilderment at why people laugh when he says that he spent the war in Oklahoma, pointing out with mock pride that no Japanese plane ever got past Tulsa deep in the center of the continental US. Gobel also began to get some unexpected laughs, being unaware that Dean Martin had begun flicking his cigarette ashes into Gobel's drink. Observing all of this, Carson finally asked rhetorically, "Exactly what time did I lose control of the show?!"

In the 1970s, Gobel was a regular panelist on the television game show Hollywood Squares hosted by Peter Marshall. He was also the voice of Father Mouse in the 1974 Christmas special Twas the Night Before Christmas, and sang the song Give Your Heart a Try in that production. He also made a guest appearance on Hee Haw in 1976. In the early 1980s Gobel played Otis Harper, Jr., the mayor of Harper Valley in the television series based on the film Harper Valley PTA.

The centerpiece of Gobel's comedy show was his monologue about his supposed past situations and experiences, with stories and sketches allegedly about his real-life wife, Alice (nicknamed "Spooky Old Alice"), played by Actress Jeff Donnell. Gobel's hesitant, almost shy delivery and penchant for tangled digressions were the chief sources of comedy, more important than the actual content of the stories. His monologues popularized several catchphrases, notably "Well, I'll be a dirty bird" (spoken by the Kathy Bates character in the 1990 film Misery), "You don't hardly get those anymore" and "Well then there now" (spoken by James Dean during a brief imitation of Gobel in the 1955 film Rebel Without a Cause and as part of the closing lyric in Perry Como's 1956 hit record "Juke Box Baby").

George Gobel died in 1991, shortly after undergoing heart surgery. He was survived by his wife Alice and three children. He is interred in the San Fernando Mission Cemetery in Mission Hills, Los Angeles, California.