Williams' solo career began in 1953. He recorded six sides for RCA Victor's label "X," but none of them were popular hits.

After finally landing a spot as a regular on Steve Allen's Tonight Show in 1954, he was signed to a recording contract with Cadence Records, a small label in New York run by conductor Archie Bleyer. His third single, "Canadian Sunset" reached #7 in the Top Ten in August 1956, and was soon followed by his only Billboard #1 hit, "Butterfly" (a cover of aCharlie Gracie record on which Williams imitated Elvis Presley) in February 1957. More hits followed, including "The Hawaiian Wedding Song" (U.S. #11), "Are You Sincere" (U.S. #3 in February 1958), "The Village of St. Bernadette" (U.S. #7 in December 1959), "Lonely Street" (U.S. #5 in September 1959), and "I Like Your Kind Of Love" with Peggy Powers (U.S. #8 in May 1957) before Williams moved to Columbia Records in 1961, having moved from New York to Los Angeles and gaining another hit with "Can't Get Used to Losing You" (U.S. #2). In terms of chart popularity, the Cadence era was Williams' peak although songs he introduced on Columbia became much bigger standards. Two top ten hits from the Cadence era, "Butterfly" and "I Like Your Kind of Love" were apparently believed to not suit Williams' later style; they were not included on a Columbia reissue of his Cadence greatest hits in the 1960s.

In 1964, Williams ultimately became the owner of the Cadence master tapes, which he occasionally licensed to Columbia, including not only his own recordings, but those of his fellow Cadence-era labelmates, The Everly Brothers, Lenny Welch, The Chordettes, and Johnny Tillotson. In 1968, although he was still under contract with Columbia for his own recordings, Williams formed a separate company called Barnaby Records not only to handle reissuing of the Cadence material, especially that of The Everly Brothers (one of the first Barnaby LPs was a double LP set of the brothers long out of print Cadence hits) but new artists as well. Barnaby also had several Top 40 hits in the 70s with novelty artist Ray Stevens (who had done a summer replacement show for Williams in 1970), including Top 10s such as "Everything Is Beautiful" in 1970, and "The Streak" in 1974.

Also in 1970, Barnaby signed and released the first album by an unknown singer-songwriter named Jimmy Buffett ("Jimmy Buffett Down to Earth") produced by Travis Turk. Columbia initially was the distributor for Barnaby, but later distribution was handled first by MGM Records and then GRT. Once Barnaby ceased operating as a working record company at the end of the 1970s, Williams licensed the old Cadence material to various other labels (such as Varese & Rhino in the U.S.) after 1980.

During the 1960s, Williams became one of the most popular vocalists in the country and was signed to what was at that time the biggest recording contract in history. He was primarily an album artist, and at one time he had earned more gold albums than any solo performer except Frank Sinatra, Johnny Mathis and Elvis Presley. By 1973 he had earned as many as 18 gold album awards. Among his hit albums from this period were Moon River, Days of Wine and Roses (number one for 16 weeks in mid-1963), The Andy Williams Christmas Album,Dear Heart, The Shadow of Your Smile, Love, Andy, Get Together with Andy Williams, and Love Story. These recordings, along with his natural affinity for the music of the 1960s and early 1970s, combined to make him one of the premier easy listening singers of that era. In the UK, Williams continued to reach high chart status until 1978. The albums Can't Help Falling In Love (1970), Andy Williams Show(1970) Home Lovin Man ( #1 1971), Solitaire (1973), The Way We Were (1974) and Reflections (1978) all reached the Top 10.

Williams forged an indirect collaborative relationship with Henry Mancini, although they never recorded together. Williams was asked to sing Mancini and Johnny Mercer's song "Moon River" at the 1962 Oscar Awards (where it won), and it quickly became Williams' theme song. ("Moon River" was never a chart hit for Williams).^[10] The next year Williams sang "Days of Wine and Roses" which was written by Mancini and Mercer (this song also won). Two years later, he sang Mancini's "Dear Heart" at the 1965 awards and "The Sweetheart Tree" (also written with Mercer) at the 1966 awards.

On August 5, 1966, the 14-story, 700 room Caesars Palace casino and nightclub opened in Las Vegas, Nevada with the stage production of "Rome Swings", in which Williams starred. He performed live to a sold out crowd in the Circus Maximus showroom. He headlined for Caesars for the next twenty years.

In 1968, Columbia released a 45-rpm record of two songs Williams sang at the funeral of Robert F. Kennedy, a close friend: "Ave Maria" and "The Battle Hymn of the Republic". These were never released on a long-playing record.

Williams also competed in the teenage-oriented singles market as well and had several charting hits including "Can't Get Used to Losing You", "Happy Heart", and "Where Do I Begin", the theme song from the 1970 blockbuster film, Love Story. In addition Williams hit the Top 10 of the UK Singles Chart with, "Almost There" (1965), "Can't Help Falling In Love" (1970), "Home Lovin' Man" (1970) and "Solitaire" (1973).

Both Williams and Petula Clark recorded "Happy Heart" at the same time, just prior to his guest appearance on her second NBC-TV special. Unaware that she, too, was releasing the song as a single, he asked to perform it on the show. The exposure ultimately led to his having the bigger hit with the tune. The song "Happy Heart" is played during the final scene, and throughout the end credits, of the Danny Boyle film Shallow Grave .

Building on his experience with Allen and some short-term variety shows in the 1950s, he became the star of his own weekly television variety show in 1962. This series, The Andy Williams Show, won three Emmy Awards for outstanding variety program. Among his series regulars were the Osmond Brothers. He gave up the variety show in 1971 while it was still popular and retrenched to three specials per year. His Christmas specials, which appeared regularly until 1974 and intermittently from 1982 into the 1990s, were among the most popular of the genre. Williams has recorded eight Christmas albums over the years and has been penned as Mr. Christmas.

Williams hosted the most Grammy telecasts, from the 13th Annual Grammy Awards in 1971 through the 19th Annual Grammy Awards in 1977, totaling seven consecutive shows. He returned to television to do a syndicated half-hour series in 1976–77.

In the early 1970s, when the Nixon Administration attempted to deport John Lennon, Andy Williams was an outspoken defender of the Beatle's right to stay in the United States.

A caricature of Andy Williams is included in the montage of caricatures displayed on the cover of Ringo Starr's 1973 album, "Ringo".

Williams also sang the national anthem at Super Bowl VII in 1973 with Little Angels of Holy Angels Church in Chicago, Illinois