Her father was a minister, and when she joined a local stock company as a youngster she changed her name to avoid embarrassing her family. She worked in vaudeville and debuted on Broadway in 1916. Her film debut was in "A House Divided" (1931). She repeated her stage role in "Dead End" (1937) as Baby Face Martin (Humphrey Bogart)'s mother, which led to a number of slum mother parts. She played very strong role of Lucy, the dude ranch operator in "The Women" (1939). She achieved popularity as a comedienne in six 1940s movies made with Wallace Beery e.g., "Barnacle Bill" (1941). The character which would dominate her remaining career was established when she played Ma Kettle in "The Egg and I" (1947), for which she received an Academy Award nomination for best supporting actress. She began her co-starring series with Percy Kilbride the following year in "Feudin', Fussin' and A-Fightin'" and continued through seven more. Her last movie was a "Kettles", though without Kilbride: "The Kettles on Old MacDonald's Farm" (1957).
She attended Franklin College, in Franklin, Indiana. Had been known to wear white gloves and a surgical mask for fear of germ contamination. Long-time companion of actress Spring Byington. There were a total of 10 movies in which Main played the character of "Ma Kettle". Where she did co-star with Percy Kilbride in "Feudin', Fussin' and A-Fightin'", it is not a Kettle film.