Addressing the challenges of melanoma, including its aggressive nature and treatment resistance. This study explores the application of silver nanoparticles (AgNPs) synthesized via conventional and green methods. By examining proteomic changes in A375 melanoma cells, we identify key disruptions in cell viability and gene activity. The DIA MS/SWATH MS analysis generates a set of differentially expressed proteins with respect to AgNPs. This allows us to identify new potential regulatory mechanisms and molecular pathways. AgNP exposure leads to oxidative stress, mitochondrial dysfunction, and activation of apoptosis pathways, revealing the potential of AgNPs in melanoma treatment. This comprehensive analysis highlights the promise of eco-friendly nanoparticle synthesis in developing effective anti-cancer therapies.