In the early seventeenth century, El Greco and his studio produced several series of Apostles, or Apostolados, generally consisting of thirteen pictures (twelve of the Apostles and one of the Saviour). Conceived as a series of portrait-like easel paintings, they reflected the new Counter-Reformation emphasis on the individual personalities of the Apostles, and as such were an important iconographic innovation in Spanish art. Only two complete series are known that show the hand of El Greco, one in the Cathedral of Toledo and the other in the Museo del Greco, also in Toledo (both dated to the circa 1605-1610). It is only in the first set that Saint Luke appears (possibly because he was not one of the original Apostles) and the present painting is a copy after this work. According to popular belief, Saint Luke was known as a painter who made several portraits of the Madonna and Child. Although from the late Middle Ages painters would often depict themselves as Saint Luke, it is unlikely that the Toledo Saint Luke is a self-portrait of El Greco, who would have been in his sixties at the time of its execution.
In a letter dated 10 October 1928, August L. Mayer stated his belief that the present work was by El Greco, while Harold Wethey considered it to be 'by El Greco or possibly with some assistance' (letter dated 26 August 1979).