Forming The Royal Canadians in 1924 with his brothers Carmen, Lebert, and Victor and other musicians from his hometown, Lombardo led the group to international success, billing themselves as creating "The Sweetest Music This Side of Heaven." The Lombardos are believed to have sold more than 300 million phonograph albums during their lifetimes.
Lombardo's orchestra played at the Roosevelt Hotel in New York City from 1929 to 1959, and their New Year's Eve broadcasts (which continued with Lombardo until 1976 at the Waldorf Astoria) were a major part of New Year's celebrations across North America. Even after Lombardo's death, the band's New Year's specials continued for air two more years on CBS.
In 1938, he became a naturalized citizen of the United States. The Royal Canadians were noted for playing the traditional song "Auld Lang Syne" as part of the celebrations. Their recording of the song still plays as the first song of the new year in Times Square.
Although Lombardo's big band music was viewed by some in the jazz and swing community of the day as "corny," trumpeter Louis Armstrong famously enjoyed Lombardo's music.
Lombardo was inducted into the Long Island Music Hall of Fame in 2007.
In his later years, Lombardo lived in Freeport, Long Island, New York, where he kept his boat, Tempo IV. He also invested in a nearby seafood restaurant (or clam shack) originally called "Liota's East Point House." It was soon "Guy Lombardo's East Point House." Lombardo later became an earlier promoter and musical director of Jones Beach Marine Theater, which is a still-popular concert venue south of Freeport.

The Guy Lombardo Museum
is located near Wonderland Gardens, a venue closely associated with Lombardo and the Royal Canadians. (Wonderland Gardens was destroyed by a fire in August 2005.) Nearby there is also a bridge named after him, as well as Lombardo Avenue in north London near the University of Western Ontario.
The portion of Grove Street in Freeport south of Sunrise Highway is known as Guy Lombardo Avenue. The birth home of Guy Lombardo is still standing in London, Ontario, at 202 Simcoe Street.
A plaque to the Lombardos has been moved from the exterior wall of the Labatt Retail Store at Richmond and Horton streets in London to the store's entranceway off the parking lot, denoting the site of a subsequent home of the Lombardos.
In the film Monty Python and the Holy Grail, the taunting French soldiers claim that their castle is owned by Guy de Lombard, whom the script's authors named in tribute to Lombardo.
In the song "Marry The Man Today" in Frank Loesser's musical "Guys and Dolls" Guy Lombardo is one of "the better things" that Sarah and Adelaide decide they will make their husbands appreciate to make them more genteel. The tongue-in-cheek list also includes Reader's Digest and Ovaltine.
The Porky Pig cartoon Porky at the Crocadero features a group called "Guy Lumbago and the Boiled Kanadians".
Grindcore band Anal Cunt recorded two different versions of their song Guy Lombardo, included in Morbid Florist and Everyone Should Be Killed.
The co-owner and promoter of wrestling promotion the NWA Indiana wrestles under the name Guy Lombardo, a name given to him by his trainer.
In Viva Smart, an episode of Get Smart, a password phrase used between two spies is: "Herb Alpert takes trumpet lessons from Guy Lombardo".