Ultraviolet radiation (UVR) is involved in both sunburn and the development of skin cancer, which has a high incidence worldwide. Strategies to reduce these effects include the use of photoprotective substances. The aim of this work was to investigate the photoprotective effect of verbascoside isolated from the methanolic extract of Buddleja cordata (BCME) in SKH-1 mice exposed to acute and chronic UV-B radiation. The mouse dorsal area was evaluated macroscopically and microscopically for diagnosis; verbascoside penetration into mouse skin was investigated in vivo by the tape stripping method. After acute UV-B exposure, 100% of irradiated mice that had been protected with verbascoside showed no signs of sunburn or of inflammatory processes. After chronic exposure, 100% of unprotected mice showed skin carcinomas; in contrast, in mice topically treated with either BCME or verbascoside, the presence of lesions was decreased by 90%. These results prove that verbascoside penetrates through the skin of mice and suggest that verbascoside and BCME may potentially prevent photodamage on mice’s skin after acute and chronic UVR exposure.