She first studied with Antoine François Marmontel and Charles-Valentin Alkan's son, Élie-Miriam Delaborde, at the Conservatoire de Paris, and later with Ernst Jedliczka in Berlin.

After her divorce from Loutzky and the 1900 hurricane that claimed her family's business, she returned to the United States and tried to carve out a career as a pianist.

She hired the hall, the orchestra, and conductor Walter Damrosch, and made an overwhelming impression with her performance of Tchaikovsky's Piano Concerto No.

Samaroff discovered Leopold Stokowski (1882–1977) when he was church organist at St. Bartholomew's in New York and later conductor of the Cincinnati Symphony Orchestra.

At that time, Samaroff was much more famous than her husband and was able to lobby her contacts to get Stokowski appointed in 1912 to the vacant conductor's post at the Philadelphia Orchestra, thus launching his international career.

She was the second pianist in history, after Hans von Bülow, to perform all 32 Beethoven piano sonatas in public, preceding Artur Schnabel (who did the series in 1927) by several years.

Called "Madam" by her students, she was an advocate for them, supplying many of her Depression-era charges with concert clothes and food, or helping to subsidize their rent or letting them live with her in her New York apartment.

She herself said that the best pianist she ever taught was the New Zealander Richard Farrell, who also died at age 31, in a motor vehicle accident in England in 1958.