Objective Verruca is a dermatological disease caused by human papillomavirus (HPV), and includes conditions such as verruca vulgaris and condyloma acuminatum. Although treatments are available to remove skin warts, effective therapies are still lacking. Because of species specificity, the development of animal models of HPV infection has been limited. In this study, mouse papillomavirus (MmuPV1) was used to infect immunodeficient mice to establish a murine model of skin papillomatous hyperplasia. Methods After anesthesia, the tail skin was gently scraped with a blade to produce a slight wound, which was then inoculated with 1. 5 × 10⁸ copies of viral DNA. Changes in the tail skin were observed, viral DNA and load were examined, and pathological analysis was performed. Results Sixteen weeks post-infection with MmuPV1, papillomatous hyperplasia with hyperkeratosis had developed at the infection sites. HE staining showed hyperplasia of squamous epithelium and vacuolar degeneration in the spinous and granular layers. MmuPV1 E4 transcript was detected by RNAscope in situ hybridization. MmuPV1 DNA in the samples was detected by PCR amplification of the E2 gene. Viral DNA was tested in all MmuPV1-infected NU/ NU mice samples by qRT-PCR. Conclusions Our result suggest that MmuPV1 skin infection in mice mimics HPV disease, and can therefore serve as a useful model for studying the pathogenesis and natural history of HPV infection.