James Kern Kyser, known professionally as Kay Kyser, was born on June 18, 1905, in Rocky Mount, North Carolina. He was the son of pharmacists Paul Bynum Kyser and Emily Royster Kyser, with his mother being the first registered female pharmacist in the state. Kyser attended the University of North Carolina at Chapel Hill, where he graduated with a Bachelor of Arts degree in 1928. During his time at university, he was a cheerleader and served as senior class president.

Kyser's career in music began when he took over as bandleader from Hal Kemp, a fellow university student. Although he initially struggled, Kyser's band gained popularity, particularly after a successful stint at the Blackhawk Restaurant in Chicago. He became widely known for his radio program "Kay Kyser's Kollege of Musical Knowledge," which combined quiz elements with musical performances. The show aired on NBC Radio from 1939 to 1949 and was a significant success.

During the big band era, Kyser's orchestra produced 11 number one records, and he became known for his entertaining style, often using catchphrases and humor in his performances. Notable members of his band included vocalist Harry Babbitt, cornetist Merwyn Bogue (a.k.a. Ish Kabibble), and saxophonist Jack Martin.

Kyser married Georgia Carroll, a vocalist in his band, and they had three daughters. After retiring from music in 1950, he dedicated himself to Christian Science and other philanthropic activities. Kyser passed away on July 23, 1985, in Chapel Hill, North Carolina. His legacy includes contributions to both the music industry and his community, particularly through his work in public television and health affairs at the University of North Carolina.