He was the first Chinese-American contract player signed by RKO, Universal Pictures and Metro-Goldwyn-Mayer and was one of the most prominent Asian actors of American cinema in the mid-20th century.

His father, Lee Luke, was born in San Francisco in 1880, and traveled to China several times where he married Keye's mother, Down Cook.

He also created illustrations for the books The Unfinished Song of Achmed Mohammed by Earle Liederman, Blessed Mother Goose by Frank Scully and an edition of Messer Marco Polo by Brian Oswald Donn-Byrne (unpublished).

The unfinished Oland-Luke film Charlie Chan at the Ringside was completed as Mr. Moto's Gamble (1938), with Luke now opposite Peter Lorre.

Metro-Goldwyn-Mayer cast him in a recurring role in its Dr. Kildare film series, and Monogram Pictures featured him in its Frankie Darro comedies and starred him as Mr. Wong in Phantom of Chinatown.

Unlike Boris Karloff, who had preceded him in the Mr. Wong role, Luke played the detective without any exotic touches.

Luke had a featured Broadway role in the Rodgers and Hammerstein musical Flower Drum Song, directed by Gene Kelly in 1958.

He dubbed the voice of the evil Mr. Han (played by Shih Kien) in Enter the Dragon (1973) starring Bruce Lee.

He was a regular cast member in two short lived sitcoms, Anna and the King (1972) starring Yul Brynner and Sidekicks (TV 1986–87).

He also voiced several other animated characters including Brak in Space Ghost (1966-68) and Zoltar/The Great Spirit/Colonel Cronus in Battle of the Planets (1978-80).

Luke played Governor Donald Cory in episode 71[6] of the original Star Trek entitled "Whom Gods Destroy[7] (1969),[6] and was going to play Doctor Noonien Soong in the Star Trek: The Next Generation episode "Brothers" but illness prevented him from doing so; Brent Spiner ultimately took over the role.

[citation needed] In the Fractured Fairy Tales episode "The Enchanted Fly," one of the rewards offered to the man who would rescue and marry the princess is "an autographed picture of Keye Luke."