Niclosamide, an FDA-approved anti-helminthic drug, has attracted attention for its potential to target multiple cancer-related pathways. This study evaluated the chemopreventive effect of niclosamide in a DMBA/TPA-induced mouse model of skin carcinogenesis and explored its mechanisms using integrated biological and network-based approaches. Mice were treated with niclosamide at 15, 30, and 45 mg/kg and compared with healthy, disease, and standard therapy controls. Tissue and serum analyses were conducted to measure markers of inflammation (TNF-α, IL-6, IL-1β), oxidative stress (MDA, SOD, GSH), apoptosis (caspase-3, Bax/Bcl-2), and angiogenesis (VEGF). Niclosamide reduced tumor volume in a dose-dependent manner, suppressed inflammatory cytokines, restored antioxidant levels, activated apoptotic signaling, and downregulated VEGF expression. A protein-protein interaction network was constructed using eleven experimentally relevant genes to identify key regulatory modules. Network topology and enrichment analysis revealed two functional clusters associated with inflammation, apoptosis, and redox homeostasis. Hub genes such as TNF, IL6, CASP3, and GPX1 highlighted potential interactions among pathways affected by niclosamide. Thus, these findings suggest that niclosamide may exert anticancer effects by modulating interconnected pathways related to inflammation, oxidative stress, apoptosis, and angiogenesis, supporting its potential for further investigation as a repurposed therapeutic candidate for skin cancer.