Wood began his career at the Handicraft Guild of Minneapolis where he studied wood and metal works. He opened and worked in a handicraft shop in Iowa upon completion of his studies, but an unflagging interest in painting took him to the Art Institute of Chicago and to The Acad,mie Julian in Paris where he studied art and painting.

In 1928, he went to Munich to supervise a commission for stained glass window works and discovered "Netherlandish" paintings. He abandoned his earlier, impressionistic style of painting and picked up the more detailed manner of Dutch masters.

Wood's artwork was brought to national attention in 1930 when his painting, "American Gothic," won a bronze medal at the Art Institute of Chicago. "American Gothic" aroused controversy among the art community who were upset with Wood's caricatures of "plain, country folk." During the 1930s, Wood supervised many Iowa projects for the Federal Arts Project. He remained in Iowa for the remainder of his life, teaching fine arts at the University of Iowa.

After his death, there was a retrospective exhibition of his works held at the Whitney Museum of American Art.