The objective of the present study was to evaluate the development of simvastatin-loaded pH-responsive liposomes (SIM-LIPO) and its efficacy on prostate cancer (PCa) cells in vitro. Drug release study showed burst release of SIM at pH 5.5 within 4 h, whereas at pH 7.4 sustained release was observed till 48 h. Infrared spectroscopy showed the absence of unwanted interaction between drug and excipients, whereas, differential scanning calorimetry revealed molecular dispersion of SIM post incorporation within the liposomal matrix. Cell viability assay showed comparable cytotoxicity between free SIM and SIM-LIPO. Cell internalization assay demonstrated successful uptake of optimized formulation by PC-3 cells. Microscopic evaluations revealed reactive oxygen species generation and apoptosis induction in PC-3 cells after SIM and SIM-LIPO treatments. SIM-LIPO demonstrated superior cell cycle arrest at the G0/G1 phase in comparison to free SIM. These results demonstrated that pH-responsive SIM-LIPO could be a promising therapeutic approach for PCa management.