From Detroit, at the urging of Louis Armstrong, Jeffries moved to Chicago where he performed in various clubs. One of his first gigs was in a club allegedly owned by Al Capone. Jeffries began his career working with Erskine Tate and his Vendome Orchestra. Tate signed the 19-year-old Jeffries to a contract with his Orchestra at the Savoy Ballroom in Chicago. His break came during the 1933 Chicago World's Fair A Century of Progress International Exposition singing with the Earl Hines Orchestra on Hines' national broadcasts live from the Grand Terrace Cafe. His first recordings were with Hines in 1934, including "Just to be in Carolina". By 1940, he was singing with the Duke Ellington Orchestra and then recorded with him from 1940 to 1942. His 1940 recording of "Flamingo" with Ellington, released in 1941, sold more than 14 million copies in its day. His name had been Herbert Jeffrey, but the credits on the record mistakenly called him Jeffries, so he renamed himself to match the typo. During his time with the Duke Ellington Orchestra as a lead vocalist, Jeffries proved his talent as a mature singer, demonstrating his wide vocal range in such songs as "I Don't Know What Kind of Blues I've Got," "The Brownskin Gal," and "Jump for Joy" (all 1941). The 1944 single "My Little Brown Book" by Ellington and his Famous Orchestra, on which Jeffries provided vocals, reached No. 4 on Billboard R&B chart.

In his teens Jeffries developed a fine voice; initially he sang in higher registers. He started out his singing career as a lyrical tenor, but, on the advice of Duke Ellington's longtime music arranger, Billy Strayhorn, he lowered his range to mimic the vocal stylings of crooner Bing Crosby. Jeffries became a "silken, lusty baritone," according to music critic Jonny Whiteside.

In 1945, Jeffries had a hit on the Billboard R&B chart with "Left A Good Deal In Mobile" (No. 2), on which he was accompanied by pianist Joe Liggins and his band Honeydrippers. Then, he moved to Europe and performed there for many years, including at nightclubs he owned. He was back in America by the 1950s, recording jazz records again, including 1957 collection of ballads, Say It Isn't So.

In 1995, at age 81, he recorded The Bronze Buckaroo (Rides Again), a Nashville album of songs on the Warner Western label.

Almeida was first introduced to the jazz public as a featured guitarist with the Stan Kenton band in the late 1940s during the height of its success. According to author Michael Sparke, Almeida and his fellow Kenton bandmember drummer Jack Costanzo "endowed the music of Progressive Jazz with a persuasive Latin flavor, and the music is enriched by their presence." Famed Kenton arranger Pete Rugolo composed "Lament" specifically for Almeida's cool, quiet sound, and Almeida's own composition "Amazonia" was also featured by the Kenton orchestra. Almeida stayed with Kenton until 1952.

Almeida's recording career enjoyed auspicious early success with the 1953 recordings now called Brazilliance No. 1 and No. 2 with fellow Kenton alumnus Bud Shank, bassist Harry Babasin, and drummer Roy Harte on the World Pacific label (originally entitled "The Laurindo Almeida Quartet featuring Bud Shank"). Widely regarded as "landmark" recordings, Almeida and Shank's combination of Brazilian and jazz rhythms (which Almeida labeled "samba-jazz") presaged the fusion of Latin and jazz, which is quite different in bossa nova, although jazz critic Leonard Feather credited Almeida and Shank as the creators of bossa nova sound.

Other observers note that the beat, harmonic stamp, and economy of expression were different from the bossa nova, giving Almeida and Shank's recording "...a different mood and sound...certainly valuable in its own right."

Almeida's classical solo recording career on Capitol Records began in 1954 with The Guitar Music of Spain. Almeida made a series of highly successful classical recordings produced by Robert E. Myers. Among Almeida's notable classical recordings is an album widely considered to be the first classical crossover album, the 1958 Grammy winner Duets with the Spanish Guitar with mezzo-soprano Salli Terri and flutist Martin Ruderman. In this recording, Almeida arranges standard classical and folk repertoire through the prism of several Latin musical forms, including the modenha, charo, maracatu and boi bumba. The result, according to Hi-Fi and Music Review was "...a prize winner in my collection. Laurindo Almeida's guitar playing captures the keen poignancy and rhythmic élan of Brazilian music with superb assurance and taste ...". The recording was nominated for two Grammy Awards and won for Best Classical Engineering for Sherwood Hall III at the first Grammy Awards ceremony. In her recent memoir Simple Dreams, singer Linda Ronstadt discusses Duets With the Spanish Guitar and notes that her aunt, the renowned Spanish singer was a friend of vocalist Salli Terri: "Knowing I wanted to sing, Aunt Luisa had sent me a recording, Duets with the Spanish Guitar, which featured guitarist Laurindo Almeida dueting alternately with flautist Martin Ruderman and soprano Salli Terri. It became one of my most cherished recordings."

Of Almeida's five career Grammys, four were awarded in classical categories. His classical recording discography also includes the debut recordings of two major guitar works, Heitor Villa-Lobos' Guitar Concerto and Radamés Gnattali's Concerto de Copacabana.

In 1964, Almeida again expanded his recording repertoire by joining forces with the Modern Jazz Quartet on Collaboration (Atlantic Records), which combined classical with jazz, called "chamber jazz." Almeida also toured with the MJQ, both in the 1960s and again in the 1990s.