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SeMet-Pro-Ser (Se-MPS), identified from selenium-enriched brown rice protein hydrolysates, shows strong free radical scavenging capacities and hexavalent chromium [Cr(VI)] reduction activity. This study explored the protective effect and mechanism of Se-MPS on potassium dichromate (K2Cr2O7)-induced toxicity in L-02 hepatocytes. Exposure of L-02 hepatocytes to K2Cr2O7 drastically decreased the cell viability and caused cell apoptosis, which was effectively suppressed by Se-MPS treatment in a dose-dependent manner. Se-MPS significantly prevented the increase of reactive oxygen species (ROS) and malondialdehyde (MDA) generation, the decrease of antioxidant enzyme activities; and the depletion of reduced glutathione (GSH) induced by K2Cr2O7. In addition, Se-MPS could alleviate K2Cr2O7- induced apoptosis as assessed by mitochondrial membrane potential and caspase family. The expression levels of apoptosis-related proteins Bax and cytochrome C were significantly downregulated, and anti-apoptotic protein Bcl-2 was significantly upregulated in the Se-MPS plus K2Cr2O7 group. This study provided further insights into Se-MPS in resisting K2Cr2O7-induced cytotoxicity.