Wood's inspiration came from what is now known as the American Gothic House, and his decision to paint the house along with "the kind of people I fancied should live in that house." When asked what, American Gothic was about, Wood often said that it was really about architecture. The house seemed to him typically American. He found the house in Eldon, Iowa and made several sketches. In the painting the pitch fork and the shirt connect us to the lines of the building behind. The pattern on the woman’s dress relates to the shades in the window. The elongated faces of the models go with the elongated windows.

The figures were modeled by Wood's sister, Nan Wood Graham, and his dentist, Dr. Byron McKeeby. Wood’s first choice for a female model was his mother, Hattie. However, he was concerned that posing at length would be too much for her. So, in her stead his sister Nan sat in. Nan, was embarrassed at being depicted as the wife of someone twice her age - and began telling people that the painting was of a man and his daughter. 

The painting came to be seen in the Great Depression as a depiction of steadfast American pioneer spirit. Wood was quoted as saying, "All the good ideas I've ever had came to me while I was milking a cow."  Wood entered his painting in a competition at the Art Institute of Chicago. It received the bronze medal and a $300 cash prize.  As the painting gained attention it was reproduced in newspapers. Iowans were furious at their depiction.  One farm-wife threatened to bite Wood's ear off.  To that Wood said, He didn't paint a caricature of Iowans but rather “a depiction of Americans”.