Understanding the genetic architecture of adaptation is of great importance in evolutionary biology. U.S. weedy rice is well adapted to the local conditions in U.S. rice fields. Rice blast disease is one of the most destructive diseases of cultivated rice worldwide. However, information about resistance to blast in weedy rice is limited. Here, we evaluated the disease reactions of 60 U.S. weedy rice accessions with 14 blast races, and investigated the quantitative trait loci (QTL) associated with blast resistance in two major ecotypes of U.S. weedy rice. Our results revealed that U.S. weedy rice exhibited a broad resistance spectrum. Using genotyping by sequencing, we identified 28 resistance QTL in two U.S. weedy rice ecotypes. The resistance QTL with relatively large and small effects suggest that U.S. weedy rice groups have adapted to blast disease using two methods, both major resistance (R) genes and QTL. Three genomic loci shared by some of the resistance QTL indicated that these loci may contribute to no-race-specific resistance in weedy rice. Comparing with known blast disease R genes, we found that the R genes at these resistance QTL are novel, suggesting that U.S. weedy rice is a potential source of novel blast R genes for resistant breeding.