We used AML12 normal mouse liver cells as a model to investigate the ameliorating effect of lycopene on patulin-induced apoptosis. Control and treated cells were subjected to CCK-8 assays, and the protective effect of lycopene on cell membranes was detected by lactate dehydrogenase (LDH) release assays. Levels of reactive oxygen species (ROS) and superoxide dismutase (SOD) were also measured. Cell morphological changes were observed via fluorescence microscopy. Apoptosis rates were detected via Annexin V-EGFP/PI staining, and expression levels of apoptosis-related proteins, including Chop, Grp78, Caspase-12, Caspase-9, Caspase-3, Bcl-2, and Bax, were determined via Western blotting. CCK-8 assay results revealed that patulin-induced apoptosis of AML12 cells could be significantly inhibited by lycopene. Cell viability was 57.09% after treatment with 6 μmol•L-1 patulin. When cells were pre-incubated with lycopene for 24 hours and treated with 6 μmol•L-1 patulin, cell viability was 73.84%. LDH release by cells pretreated with lycopene was 29.25% lower than that of cells incubated with patulin alone, indicating that cell membrane integrity can be effectively protected by lycopene. Annexin V-EGFP/PI staining showed that lycopene could reduce the patulin-induced apoptosis and necrosis rate from 38.24% to 25.57%, with the prevalence of late-stage apoptotic cells decreasing by 9.37%. Cell redox system index measurements showed that the SOD activity decline caused by patulin could be inhibited by lycopene, thereby reducing excessive ROS production. These results demonstrate that patulin-induced apoptosis of AML12 normal mouse liver cells could be significantly inhibited by lycopene through modulation of the endoplasmic reticulum stress pathway. These finding provide a theoretical foundation for lycopene’s hepatoprotective mechanism.