Skin cancer is a growing global health concern, marked by high incidence and significant mortality, particularly in aggressive melanoma subtypes. In this study, we employed an integrative network pharmacology and molecular docking approach to evaluate the anticancer potential of Nigella sativa (black seed) against skin cancer. Initially, 13 active compounds were identified from N. sativa based on stringent pharmacokinetic criteria. Target prediction using SwissTargetPrediction, integrated with 9,697 skin cancer-associated genes from GeneCards and DisGeNET, revealed 303 overlapping targets implicated in critical oncogenic processes. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses via the DAVID database identified 780 biological processes, 87 cellular components, and 278 molecular functions. Enriched pathways included the positive regulation of the MAPK cascade, EGFR signaling, angiogenesis, and several other pathways central to skin cancer pathogenesis. The compound-target network further underscored the polypharmacological nature of N. sativa, highlighting hub genes. Molecular docking studies were conducted to validate the interactions of select bioactive compounds with key receptors (AR, CDK4, EGFR, MAPK1, and MAPK3). Among the compounds, 24-methylenelophenol (CID: 5283640) demonstrated the strongest binding affinities, with energies of –9.1 kcal/mol for both EGFR and MAPK3, –9.0 kcal/mol for CDK4, –8.2 kcal/mol for MAPK1, and –7.4 kcal/mol for AR. Cycloeucalenol (CID: 101690), Obtusifoliol (CID: 65225) and Lophenol (CID: 160482) also exhibited potent interactions, particularly with EGFR, MAPK1, MAPK3 and CDK4, supporting their potential to disrupt tumor proliferation and survival signaling. Collectively, these findings indicate that N. sativa’s bioactive compounds can modulate multiple cancer-related pathways, offering a promising multi-target strategy for skin cancer therapy. This computational study lays a robust foundation for subsequent in vitro and in vivo validations and paves the way for the development of novel, less toxic therapeutic regimens against skin cancer.