Fiske made her New York debut at the age of five and for the next few years played children's roles—e.g., Eva in Uncle Tom's Cabin. She made her first appearance as an adult actress in 1882. In 1890 she married the playwright and theatrical manager Harrison Grey Fiske (Fiske, Harrison Grey). Her performance of Tess in an 1897 dramatization of Thomas Hardy's novel Tess of the D'Urbervilles was her first notable success. About this time she also began to specialize in the plays of Ibsen and William Shakespeare, and her interpretations of Ibsen's heroines were especially acclaimed.

Fiske's most important roles during the period in which her husband managed the Manhattan Theatre, New York, were in Ibsen's Hedda Gabler (1903) and Rosmersholm (1907), Paul Heyse's Mary of Magdala (1904), Langdon Mitchell's Becky Sharp (1904) and The New York Idea (1906), and Edward Sheldon's Salvation Nell (1908). She toured in Ibsen's Ghosts in 1927 and in Becky Sharp in 1931.