Ladnier was born in Florenceville, Louisiana, and moved to New Orleans in his youth. He was influenced by early New Orleans trumpet/cornet players Bunk Johnson and Joe King Oliver. About 1919 he moved to Chicago, where he started making records in 1924. In 1926 he moved to New York City to join the Fletcher Henderson Orchestra. Two years later Ladnier toured Europe with Sam Wooding's band, then returned to the States to rejoin Fletcher Henderson, and then played in Noble Sissle's Orchestra, with whom he again toured Europe.
In the 1930s Ladnier co-led a band with Sidney Bechet called The New Orleans Feetwarmers, with whom Ladnier made some of his best recordings.
Tommy Ladnier died of a heart attack in New York City at the age of 39.