Her musical career began in earnest when she was discovered in 1930 by Columbia Records vice president Ted Collins, who became her longtime partner and manager and who put her on the radio in 1931. She sang the controversial top twenty song of 1931, "That's Why Darkies Were Born". She starred in the 1932 movie Hello Everybody!, with co-stars Randolph Scott and Sally Blane, and in 1943 she sang "God Bless America" in the wartime picture This is the Army. Irving Berlin had written the song in 1938 for her, and it is considered "the second National Anthem". Its popularity and constant airplay led Woody Guthrie to pen the original version of "This Land Is Your Land" in protest at the Berlin tune's unquestioning complacency.

Kate began making records in 1926; among her biggest hits were "River, Stay 'Way From My Door" (1931), "The Woodpecker Song" (1940), "The White Cliffs of Dover" (1941), "Rose O'Day" (1941), "I Don't Want to Walk Without You" (1942), "There Goes That Song Again" (1944), "Seems Like Old Times" (1946), and "Now Is the Hour" (1947). Her theme song was "When the Moon Comes Over the Mountain", the lyrics of which she helped write. Her overweight figure was the occasional butt of derision from fellow performers and managers.

She had a successful radio career with several of her own shows, the last ending in 1960. Abbott and Costello and Henny Youngman received their big breaks on The Kate Smith Variety Hour.

An unusual part of her career began on December 11, 1969, when the Philadelphia Flyers hockey team played her rendition of "God Bless America" before the game. Philadelphia beat the Toronto Maple Leafs, 6-3. The team would begin to play the song before home games every once in a while, and the perception developed that the team was more successful on these occasions, so the tradition grew. The Flyers have an incredible record of 69 wins, 18 losses and 3 ties when Kate Smith sung "God Bless America".

On October 11, 1973, she made a surprise appearance at the Flyers' home opener to perform the song in person, and received a tremendous reception. She again performed the song prior to the May 1974 game in which the Flyers clinched the Stanley Cup against Boston, and would do so on later occasions as well. Although viewed as a good luck charm to the team, there were a few losses along the way. The Flyers record when "God Bless America" was either played or sung in person was 69 wins, 18 losses, and 3 ties. Regardless of wins and losses, Ms. Smith and her song remain a special part of Flyers history. In 1987, the team erected a statue of Smith outside their arena at the time, the Wachovia Spectrum, in her memory.

In 1982, she was awarded the Presidential Medal of Freedom by President Ronald Reagan.

Kate Smith died of diabetes at the age of 79 in Raleigh, North Carolina, several years after converting to Roman Catholicism.

She never married.