Photodynamic therapy (PDT) uses a combination of photosensitizers with visible light to generate reactive species and selectively kill tumor or unwanted tissue. Znln₂S₄ nanoparticles are widely implemented in photovoltaic device materials and photolysis water catalysts owing to their unique photoelectric properties. Whether Znln₂S₄ itself can be used as an effective dye in PDT is still unknown. To determine the effects and potential mechanism of Znln₂S₄PDT on HepG2 cell apoptosis, electron microscopic analysis was performed to monitor the apoptotic morphology of HepG2 cells upon exposure to Znln₂S₄-PDT. Flow cytometry was performed to measure the apoptosis rate and intracellular ROS production. Western blot and ELISA were performed to reveal the expression changes in Bax, caspase-3 and caspase-9. Data from this work suggested that cells exhibited the typical apoptotic morphology in response to Znln₂S₄-PDT, with high apoptotic rate. The intracellular ROS production after Znln₂S₄-PDT occurred in a dose-dependent manner. Moreover, Znln₂S₄-PDT augmented the expression levels of pro-apoptosis factors, especially, Bax, caspase-3 and caspase-9. Taken together, our novel findings, Znln₂S₄-PDT elicited HepG2 cell apoptosis, suggesting Znln₂S₄ as a promising photosensitizer candidate for cancer therapy.