When alien species enter new environments, they face new challenges. They encounter new predators, parasites, or pathogenic bacteria, which leads to the rapid evolution of invasive species to adapt to new habitats, where immune-related genes play a significant role. Lithobates catesbeianus is one of the worst invasive species in the world; it rapidly spread worldwide in the 19th century and invaded China in the 1950s. We predicted the possible transmission routes of bullfrogs in China through microsatellite loci and clustered the populations at different points. We studied the adaptive selection and drift reshaping of the genetic structure of an immune genetic major histocompatibility complex (MHC) in invasive bullfrogs in 23 Chinese invasive populations (13 island and 10 mainland sites) and two American populations (Kansas and California). The Chinese bullfrog populations were divided into 6 clusters by microsatellite structure, and the MHC diversity in each cluster was different. The genetic diversity of both microsatellite and MHC genes decreased due to the bottleneck effect and the rate of diversity loss at functional and neutral loci, and there was no significant difference. We found that two MHC alleles were endemic in Chinese populations, which corresponded to distinct functional supertypes. We also analyzed the impact of environmental factors and island effects on the diversity of MHC genes. These results indicate that rapid evolution plays an important role in maintaining functionally important MHC variation during the bullfrog invasion process and provide evidence that low genetic diversity can result in successful invasion.