Aim: To develop selenium nanoparticles (SeNPs)-based delivery systems for paclitaxel (PTX) and assess their antiproliferative efficacy against cancer cells in vitro with potential mechanistic insight. Methods: Pluronic F-127 stabilized SeNPs were prepared and characterized. Effects of PTX-loaded SeNPs on lung (A549), breast (MCF7), cervical (HeLa) and colon (HT29) cancer cells were studied by viability assay complemented with flow-cytometric analyses of cell cycle, apoptosis, mitochondrial membrane potential, intracellular reactive oxygen species and caspase activity. Results: PTX-loaded SeNPs demonstrated significant antiproliferative activity against cancer cells. Cell cycle analyses of PTX-SeNPs treated cells established G₂/M phase arrest in a dose-dependent manner leading to apoptosis. Further investigation revealed disruption of mitochondrial membrane potential orchestrated with induction of reactive oxygen species leading to the activation of caspases, key players of apoptotic cell death. Conclusion: Efficient induction of apoptosis in various cancer cells by PTX-loaded SeNPs, with appropriate future studies, might lead to potential anticancer strategies.