Melanoma is the third most common malignant skin tumor and has increased in morbidity and mortality over the previous decade due to its rapid spread into the bloodstream or lymphatic system. This study used integrated bioinformatics and network-based methodologies to reliably identify molecular targets and small molecular medicines that may be more successful for Melanoma diagnosis, prognosis and treatment. The statistical LIMMA approach utilized for bioinformatics analysis in this study found 246 common differentially expressed genes (cDEGs) between case and control samples from two microarray gene-expression datasets (GSE130244 and GSE15605). Protein–protein interaction network study revealed 15 cDEGs (PTK2, STAT1, PNO1, CXCR4, WASL, FN1, RUNX2, SOCS3, ITGA4, GNG2, CDK6, BRAF, AGO2, GTF2H1 and AR) to be critical in the development of melanoma (KGs). According to regulatory network analysis, the most important transcriptional and post-transcriptional regulators of DEGs and hub-DEGs are ten transcription factors and three miRNAs. We discovered the pathogenetic mechanisms of MC by studying DEGs’ biological processes, molecular function, cellular components and KEGG pathways. We used molecular docking and dynamics modeling to select the four most expressed genes responsible for melanoma malignancy to identify therapeutic candidates. Then, utilizing the Connectivity Map (CMap) database, we analyzed the top 4-hub-DEGs-guided repurposable drugs. We validated four melanoma cancer drugs (Fisetin, Epicatechin Gallate, 1237586-97-8 and PF 431396) using molecular dynamics simulation with their target proteins. As a result, the results of this study may provide resources to researchers and medical professionals for the wet-lab validation of MC diagnosis, prognosis and treatments. Communicated by Ramaswamy H. Sarma