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Background: Skin cancer and other pathophysiological conditions of the skin are caused by inflammation. Sunset Yellow (SY) exhibits immunomodulatory characteristics, evidenced by its capacity to partially inhibit the secretion of proinflammatory cytokines, regulate immune cell populations, and modulate the activation of lymphocytes. The aim of our study was to investigate the potential anti-inflammatory properties of SY through in-silico, in vitro & physiochemical test systems, and to investigate further its implications in DMBA/TPA-induced two-step skin carcinogenesis model. Result: In vitro experiments showed that pre-treatment of SY significantly enhanced the cell viability of HaCaT cells when exposed to tertiary-Butyl Hydrogen Peroxide (tBHP). The increase in cell viability was accompanied by decreased levels of ROS, restoration of deregulated mitochondrial membrane potential, and significantly reduced DNA damage in (SY+ tBHP) treated cells. Further mechanistic investigation revealed that SY exhibited antioxidant properties. Through potentiometric titrations, the standard reduction potential (Eº) of SY was observed to be 0.211V. Additionally, this result was also confirmed using DPPH chemical antioxidant activity test. Next, we tested the implications of these findings in DMBA/TPA-induced two-step skin carcinogenesis animal model. The mice received topical application of SY (0.025%, 0.05%, and 0.1%) in conjunction with DMBA/TPA treatment for 21 weeks. The tumor incidence and body weight were evaluated at regular time intervals. SY remarkably reduced the tumor average latency period, tumor incidence, tumor yield and tumor burden in a dose-dependent manner. Finally, several in silico targets of SY were also identified, which could shed some light on the molecular mechanism triggered by SY as an antioxidant and chemo-preventive agent. Conclusions: Conclusively, we repurposed SY for the antioxidant and anti-genotoxic properties along with its chemoprotective effect on skin cancer.