Méi was born in Taizhou, Jiangsu(1894), into a family of Beijing Opera and Kūnqǔ performers. He made his stage debut at the Guanghe Theatre in 1904 when he was 10 years old. In his 50-year stage career, he maintained strong continuity while always working on new techniques. His most famous roles were those of female characters; skillful portrayal of women won him international acclaim, and his smooth, perfectly timed, poised style has come to be known in opera circles as the “Méi School.” He also played an important part in continuing the performance tradition of Kūnqǔ, noted particularly for his interpretations of Dù Lìniáng (杜丽娘; in The Peony Pavilion) and Bái Sùzhēn (白素贞; in Leifeng Pagoda) and Beauty Yu, (霸王別姬), Mei’s famous portrayal of Beauty Yu was so historically moving that he was dubbed one of the greatest vocal artists in modern China.
Méi was the first artist to spread Beijing Opera to foreign countries, participating in cultural exchanges with Japan, the United States, and other regions. He toured the world, forming friendships with the western contemporaries of his day, including Charlie Chaplin. In 1930 he toured North America, visiting Hollywood, where he welcomed by Douglas Fairbanks and Mary Pickford.  In 1935, Mei toured Europe, playing to appreciative audiences in Berlin and Moscow. Seeing Mei perform especially impressed the German playwright Bertold Brecht and influenced his concept of the alienation effect..
In July 1937, the Marco Polo Bridge Incident occurred. The Imperial Japanese Army soon occupied Beijing. The commander of the Japanese Army ordered Mei to perform for them and appointed Mei to a high rank official position. But Mei refused to sing throughout the duration of the war and endured an impoverished lifestyle until the war ended in 1945.
After 1949 he served as director of China Beijing Opera Theater, director of the Chinese Opera Research Institute, and vice-chairman of China Federation of Literary and Art Circles. Besides his autobiography, Forty Years of Life on the Stage, several of his articles and essays have been published in The Collected Works of Mei Lanfang. Recordings of his best-known performances have been published in A Selection of Beijing Operas Performed by Mei Lanfang. In 2000, the story of his life was filmed in a documentary entitled The Worlds of Mei Lanfang. Acclaimed director Chen Kaige directed Forever Enthralled, a film biography of Mei’s life, released in December 2008.