After a year as conductor of an orchestra in Berlin, Ysaÿe toured Norway, Russia, and France. From 1886 to 1897 he was professor of violin at the Brussels Conservatory. In 1894 he began in Brussels a series of orchestral concerts that introduced much new music. In the same year he founded the Ysaÿe Quartet, to which Claude Debussy dedicated the string quartet he wrote. From 1918 to 1922 Ysaÿe was conductor of the Cincinnati (Ohio) Symphony Orchestra.

Ysaÿe's playing was known for its virtuosity, expressiveness, and intensive use of vibrato. He inspired works by César Franck (who influenced his early style), Camille Saint-Saëns, Vincent d'Indy, and Gabriel Fauré. Among his own best compositions are six sonatas for unaccompanied violin, containing novel chordal and pizzicato effects. He also wrote eight violin concerti, chamber works, and an opera in Walloon dialect, Piér li Houïen (1931; “Peter the Miner”).