Non-melanoma skin cancer (NMSC) encompasses various skin malignancies, primarily basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Extended exposure to environmental elements, particularly solar ultraviolet (UV) radiation, triggers oxidative stress in skin tissues, resulting in DNA damage that is instrumental in the initiation and progression of NMSC. The imbalance between pro-inflammatory and anti-inflammatory cytokines plays a significant role in the development and progression of skin cancer. Resveratrol (RES), an organic phytoalexin present in grape skins and seeds, demonstrates promising chemopreventive and anti-neoplastic capabilities against NMSC. This research revealed that the synergistic lipid-nanocarrier incorporating RES and 5-FU showed significantly enhanced effectiveness in curtailing the proliferation of malignant cells, notably in the A431 cell line, in comparison to traditional formulations. Moreover, the study illustrated that the RES and 5-FU amalgamation exerted a combined effect in hindering cellular proliferation and triggering apoptosis in cancerous cells, as evidenced in both in vitro and in vivo experiments. Furthermore, RES is known for its antioxidant attributes, which may alleviate the impact of ROS triggered by UV exposure, thus diminishing DNA impairment and mutations. These observations imply that RES might offer chemopreventive benefits for NMSC through its role in apoptosis and mitigating oxidative stress. This research offers critical insights into the prospective utility of RES as a safer, more effective intervention for NMSC, though additional investigations are required to thoroughly decipher the underlying molecular mechanisms and clinical implications.