We examine innovation after the Great Depression using data on a century’s worth of U.S. patents and a difference-in-differences design that exploits regional variation in the severity of the economic crisis. Harder-hit areas experienced large and persistent declines in independent patenting, which lasted for the next 70 years. This decline was larger for young and inexperienced inventors and lower-quality patents. In contrast, large firms had relative innovation increases, especially for inventors with the largest declines in independent patenting. Overall, the Great Depression contributed to the decline in technological entrepreneurship and accelerated the shift of innovation into larger firms.