Born in Kenchee, Illinois, Harold Gray graduated from Purdue University in 1917. He got his first newspaper job at a Lafayette daily in 1913. He served in World War I as a bayonet instructor. After his discharge, he was employed by the Chicago Tribune. Between 1921 and 1924, he did the lettering on Sidney Smith's 'The Gumps'.
In 1924, Gray came up with a strip of his own: 'Little Orphan Otto' - soon altered to 'Little Orphan Annie', after a poem by James Whitcomb Riley that was being reprinted in the paper at that time. The strip, a soap opera about the good and evil in the world, became very popular during the 1920s. Over the years, it has been adapted into films and theatre plays.
Harold Gray experimented with other strips on the Sunday page, such as 'Private Lives', which gave humorous social commentary; and 'Maw Green', a 'Little Orphan Annie' spin-off. Then he was involved for a while with the strip of his only assistant and cousin, Ed Leffingwell's 'Little Joe', which was eventually continued by Ed's brother Robert. Gray was very devoted to his comics work, working hard and diligently. When he died on 9 May 1968, he had worked on 'Little Orphan Annie' for 45 years. He was succeeded by Tex Blaisdell.