By the age of 15, Delisle was working professionally in the music venues of Storyville, an area of brothels and clubs. He developed an early style of hot playing in the earliest days of jazz, and was an important influence on such later New Orleans jazz clarinetists as Johnny Dodds and Jimmie Noone.
In his early career "Big Eye" often played a C clarinet, as opposed to the more common B♭; the C was also used by other New Orleans clarinetists of the era, such as Alcide Nunez.
He made his only recordings in his later years in the 1940s, by which time he was often in poor health. From contemporary accounts he was past his playing prime, but still capable of producing some beautiful phrases. The recordings are available on compact disc on American Music Records. Critics describe Nelson Delisle's playing as more blues influenced and fluid compared to the stattico and raggy playing of Alphonse Picou, an older New Orleans clarinetist.