Louis Leo Prima was born in New Orleans on December 7, 1910, the second of four children in a Sicilian-American family. His father, Anthony, was the son of a Sicilian immigrant from Salaparuta, and his mother, Angelina Caravella, had come from the island of Ustica as a baby. The family lived at 1812 St. Peter Street. His mother made sure every child learned an instrument; Louis was given the violin, but he practiced obsessively on the worn cornet his older brother Leon played, and the music that pulled him in came from the clubs where Italian, Sicilian and African American New Orleanians mixed freely. He admired Louis Armstrong among the Black musicians he heard there. In 1924 he formed a band with childhood friends including the bassist Candy Candido, the clarinetist Irving Fazola and the drummer Johnny Viviano. After Warren Easton High School he decided, in the spring of 1928, to become a professional, and he spent the next several years in New Orleans pit bands, dance orchestras and his brother's Avalon Club.

The break came in 1934, when bandleader Guy Lombardo heard him at the Shim Sham club during Mardi Gras and encouraged him to go to New York. That September Prima began recording for Brunswick with Louis Prima and His New Orleans Gang, a small band with Pee Wee Russell on clarinet, Frank Pinero on piano, Jack Ryan on bass and Garrett McAdams on guitar. The records of 1935 mix Dixieland and swing; "The Lady in Red," cut in May 1935 with Russell, was a national jukebox hit. Prima played the opening night of the Famous Door on West 52nd Street, the club that became a gathering place for swing musicians. In 1936 Prima wrote and recorded "Sing, Sing, Sing (With a Swing)" for Brunswick. It became a standard of the swing era through other bands: Fletcher Henderson recorded a vocal version in August 1936, and on July 6, 1937 Benny Goodman's orchestra recorded it in Hollywood in an arrangement by Jimmy Mundy, with Gene Krupa on drums and Harry James among the trumpets. That recording ran 8 minutes and 43 seconds across two sides of a 12-inch record, Goodman's 1938 Carnegie Hall performance of it stretched to 12 minutes and 30 seconds, and the 1937 record entered the Grammy Hall of Fame in 1982.

Prima's own career in the late 1930s was less tidy. He moved to California, tried to convert the Gang into a big band, and found the new format unwelcome in New York and Los Angeles; a Chicago engagement at the Blackhawk in October 1936 went badly. He went back to a small group and returned to the Famous Door in 1937 with Frank Federico, Louis "Sherman" Masinter, Frank Pinero and the clarinetist Meyer Weinberg, then played a seven-week engagement at Billy Rose's Casa Manana in 1938. When the Famous Door reopened at 66 West 52nd Street in December 1937, Prima was the first to be given a residency, with Art Tatum playing between sets. Declared unfit for military service because of a knee injury, he kept working through the war years and recorded Italian-flavored novelties, among them "Angelina," named for his mother, "Please No Squeeza Da Banana," "Baciagaloop (Makes Love on the Stoop)" and "Felicia No Capicia." The summer of 1945 brought hits with "Bell-Bottom Trousers" and "My Dreams Are Getting Better All the Time." He also shared the writing credit on "A Sunday Kind of Love," published in 1946, and released his own recording of it in February 1947. As the big-band era wound down he recorded for RCA Victor and then Mercury, with titles such as "I Beeped When I Shoulda Bopped" in 1949, and in 1951 he signed with Columbia, where producer Mitch Miller's polished approach clashed with Prima's loose style.

In August 1948 a twenty-year-old singer from Norfolk, Virginia, Keely Smith, auditioned for his band at the Surf Club in Virginia Beach and was hired. They married in 1953. In 1954 Prima was offered an engagement in the lounge of the Sahara Hotel in Las Vegas, and he called New Orleans tenor saxophonist Sam Butera to put together a band. Butera and the musicians he brought drove west without a name for the group; asked on opening night, he answered "The Witnesses," and it stuck. The act, with Prima singing and playing trumpet, Smith standing deadpan beside him and Butera's band behind them, became one of the most popular in Las Vegas and led to a Capitol Records contract in 1955. The Wildest! was recorded in April 1956 and opened with a medley of "Just a Gigolo" and "I Ain't Got Nobody." Butera had adapted the pairing for the stage show from an earlier Prima recording; the medley became Prima's signature number, and the album also held "Jump, Jive an' Wail." The duo's "That Old Black Magic" reached No. 18 on the Billboard Hot 100 in 1958, and at the first Grammy Awards, held May 4, 1959, Smith and Prima won Best Performance by a Vocal Group or Chorus for it. They appeared in the film Hey Boy! Hey Girl! (1959), Prima recorded for Dot from 1959, and in January 1961 he was invited by Frank Sinatra to perform at President John F. Kennedy's inaugural gala. Prima and Smith divorced later that year.

Prima carried on without Smith. He brought in the singer Gia Maione, whom he married in 1963, formed his own record company in 1962, issued albums on a Prima Magnagroove label from 1963, and appeared in the film Twist All Night (also released as The Continental Twist). In 1967 he voiced the orangutan King Louie in Disney's The Jungle Book. Richard Sherman has said that he and his brother Robert wrote "I Wan'na Be Like You" with a Dixieland-flavored melody and the idea of making the king of the apes "the king of the swingers," and that they flew to Las Vegas to play the song for Prima. The original instrumental tracks by Prima, Butera and the band were replaced by a score by George Bruns, but Prima sang and scatted the part, trading lines with Phil Harris as Baloo, and he later recorded two Jungle Book albums with Harris for Disneyland Records. He suffered a heart attack in 1973. In 1975, after headaches and episodes of memory loss, he was diagnosed with a brain stem tumor; he had surgery, suffered a cerebral hemorrhage and fell into a coma from which he never recovered. He was moved back to New Orleans, passed away on August 24, 1978, and was buried in Metairie Cemetery in a crypt topped by a figure of the trumpeter-angel Gabriel. Prima received a star on the Hollywood Walk of Fame on July 25, 2010, in the year of his centenary, and Tony Bennett painted a portrait of him for the 2010 New Orleans Jazz & Heritage Festival poster. Two of his children, Lena Prima and Louis Prima Jr., became performers.

Prima's reputation divides into two parts that are best stated plainly. The part most people know is entertainment: Italian-dialect novelty songs in the 1940s, a Las Vegas lounge act built on comedy, a deadpan wife and a roaring tenor saxophone, rock-and-roll-era jump blues, twist records in the early 1960s and a Disney cartoon ape. He treated all of it as fun, and a good deal of it is exactly that. The part that earns him a place beside jazz musicians is the foundation underneath. He began on the trumpet in the Dixieland tradition of his hometown, recorded small-group Dixieland and swing with Pee Wee Russell in 1934 and 1935, wrote "Sing, Sing, Sing," which Goodman's band turned into one of the defining pieces of the swing era, and led bands rooted in New Orleans jazz, swing and jump blues for four decades. Another New Orleans trumpeter, Wingy Manone, is described in the reference literature as working in a similar mode: hot jazz trumpet leads with good-natured patter in a gravelly voice.

The 1950s Las Vegas sound owed as much to Sam Butera as to Prima. Butera, a tenor saxophonist who had played in the orchestras of Ray McKinley and Tommy Dorsey, built the rowdy small-band arrangements, including the "Just a Gigolo" and "I Ain't Got Nobody" medley, and led the Witnesses for more than twenty years. The result sits between New Orleans jazz, early rhythm and blues, and the beginnings of rock and roll, which is why the records appeal to jazz listeners and to rockabilly and swing-revival musicians alike. The Wildest! is entered in the book 1001 Albums You Must Hear Before You Die, where Will Fulford-Jones calls it irrepressible, and AllMusic has called it the gem of Prima's catalog. When Michael Cuscuna reissued it in 2002 he added four tracks recorded on September 13, 1956. Prima also stressed his Sicilian heritage at a time when ethnic performers were encouraged to downplay theirs, and that is part of his legacy as well. The later revivals of his songs show how far the repertoire traveled: Brian Setzer's orchestra won a 1999 Grammy for its version of "Jump, Jive an' Wail," and Big Bad Voodoo Daddy recorded a Prima tribute album in 2017. Butera is also cited as an inspiration for Harry Connick Jr.'s singing. Reviewers still reach for Prima when they describe the showmanship of a younger trumpeter-singer such as Benny Benack III.