Human papillomavirus (HPV) infections are prevalent skin infectious diseases. While there are no specific anti‐HPV drugs available, understanding the viral mechanisms could lead to novel therapeutic strategies. Verruca vulgaris, a common HPV infection, is frequently encountered in dermatological clinics. The HPV E2 protein, an early viral protein, has been implicated in high‐risk HPV infections by interacting with fibroblast growth factor receptor 3 (FGFR3) to inhibit viral DNA replication. However, the role of HPV E2 and FGFR3 in low‐risk HPV infections remains elusive. Our study takes HPV2, a common subtype of verruca vulgaris, to explore the proliferation and immune regulatory effects of HPV2 E2 on keratinocytes. By overexpressing FGFR3 in HPV2 E2 stable expressing keratinocytes, we assessed changes in interferon‐stimulated genes (ISGs) level and cell proliferation. Our findings revealed that HPV2 E2 induced phosphorylation of FGFR3 could activate JAK1‐STAT1 pathway, thereby enhancing antiviral immunity through the upregulation of ISGs. Furthermore, we observed co‐localization and interaction between FGFR3 and HPV2 E2 in keratinocytes. In conclusion, our study underscores the crucial role of FGFR3 in innate antiviral immunity against HPV2 infection in keratinocytes. These findings may provide a potential therapeutic target for HPV infections.