The young Loeffler learned violin from a German musician in the small town of Smjela near Kiev. The family moved to Hungary and then to Switzerland in 1873. At 14, Loeffler decided to become a musician and went to Berlin to study violin with Eduard Rappoldi, theory with Friedrich Kiel, and also to study with Joachim. He left for Paris in order to work with Joseph Massart and assimilate the pure, elegant style of the French school. He joined the Pasdeloup Orchestra and then the private orchestra of Baron Paul von Derwies. Loeffler identified closely with French culture and was embittered against Germany after his father had been imprisoned in the fortress of Ehrenbreitstein "for having told the truth about certain things concerning the Prussian government."
When the Russian Baron died, Loeffler sailed to New York in June of 1881 and played in orchestral concerts conducted by Leopold Damrosch. In 1882, he was appointed assistant conductor of the Boston Symphony Orchestra and remained there until 1903. He also taught and composed the Berceuse for violin and piano (1884), Night in the Ukraine for violin and orchestra (1891), and the lovely Harmonie du soir for low voice, viola, and piano (1897). The astonishing La mort de Tintagiles for viola d'amore and orchestra (1900) fully reveals Loeffler's deep sensibilities with its advanced harmonics and macabre, sinister impressionism.
Loeffler exclusively devoted himself to teaching and composition after 1903. In many of the works of this time, Loeffler shows his love for unusual timbres and instrumental combinations; for example, in L'archet for female voices, viola d'amore, and piano (1901); Ballade carnavalesque for flute, oboe, saxophone, bassoon, and piano (1904); the Two Rhapsodies for oboe, viola, and piano (1905); A Pagan Poem for orchestra, piano, English horn, and three trumpets obbligato (1906); and the elegantly lyrical and moving setting of Psalm CXXVII (By the Rivers of Babylon) for female chorus, cello obbligato, two flutes, organ, and harp (1907).
In 1910, Loeffler settled in Medfield where he bought a house, bred horses, read classic and contemporary literature, and enjoyed epicurian cooking. His later works reflect many influences; for example, the Gershwin and dance band-like rhythms of Clowns for expanded jazz orchestra (1928), Memories of My Childhood (1925) with its Greek Orthodox church bells and folk-like harmonica melodies, and the Five Irish Fantasies (composed variously between 1906 and 1920, with the orchestration publication in 1935) with its texts by Yeats and William Heffernan the Blind, which moves with enthralling, heroic, and rhythmic energy and creates eerie and brooding moods. Loeffler's exquisite and moving Music for Four Stringed Instruments (1917) was composed in memory of the American aviator Victor Chapman, who died in France that same year.