Montgomery began playing guitar in his late teens and played in the Lionel Hampton (Hampton, Lionel) band in 1948–50 and in Indianapolis during the 1950s, most often with his brothers Buddy (piano, vibes) and Monk (electric bass). In California in the late 1950s, he played with them in the Mastersounds and then as the Montgomery Brothers (1960–61).

Most of Montgomery's finest recordings, including The Incredible Jazz Guitar of Wes Montgomery, Movin' Along, and Full House, date from 1959–63. In the early 1960s he played briefly in a John Coltrane (Coltrane, John) group that never recorded. Beginning in 1964 a series of recordings with string orchestra and big band accompaniments became best-sellers; in concerts and on international tours, however, he led small groups and worked in a quintet with his brothers for the rest of his life.

Inspired by late-swing guitarist Charlie Christian (Christian, Charlie), Montgomery improvised in broken phrases and with a bop harmonic imagination. Instead of using a plectrum or fingers, he played guitar with the soft part of his thumb, resulting in a soft attack especially appropriate to his lyrical lines. He organized his solos by playing single-note melodies in initial choruses, in octaves in middle choruses, and in chords in climactic choruses. His solo forms especially were an influence on later guitarists, most prominently George Benson.