Survivin, a multifunctional regulator of mitosis and apoptosis, plays a central role in cancer progression and therapy resistance, making it an attractive target for anticancer drug development. In this study, a series of 4,6-diphenyl-3-cyanopyridine derivatives were designed and synthesized as potential survivin inhibitors through an integrated strategy combining 3D-QSAR modeling, molecular docking, molecular dynamics simulations, and biological evaluation. The CoMFA and CoMSIA models established reliable structure-activity relationships and provided contour-map-based guidance for rational molecular optimization. Newly designed derivatives displayed enhanced antiproliferative effects against melanoma cells, and computational analyses revealed that the most promising compound showed stable and preferential binding within the BIR domain of survivin, particularly in its dimeric form. These findings demonstrate the effectiveness of contour-guided optimization in discovering novel survivin-targeting scaffolds and highlight 4,6-diphenyl-3-cyanopyridine derivatives as promising leads for further anticancer drug development. Future studies will focus on improving selectivity, clarifying the inhibition mechanism at the molecular level, and evaluating in vivo efficacy.