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The title refers to ugly-duckling heroine Louise Fazenda, who sweats and strains at a hand laundry. One fine day, shy truckdriver Clyde Cook shows up at the establishment with a load of grimy clothes. He takes one look at Fazenda, and it's love at first sight. That's about all there is to the story, save for the Mutt-and-Jeff slapstick antics of Cook and his brawny partner William Demarest (evidently, Warner Bros. was hoping to promote Cook and Demarest as a comedy team, a la MGM's Karl Dane and George K. Arthur). Critics chose not to laugh at Simple Sis, though they admitted to being impressed by juvenile actor Billy Kent Schaffer, cast as Fazenda's troublesome kid brother.