Aim To investigate the effects of atorvastatin (Ato) on homocysteine (Hcy)-induced mitogen extracellular signal-regulated kinase (MEK)/extracellular regulatory protein kinase (ERK) pathway and myocardial mitochondrial damage in H9c2 cardiomyocytes. Methods Cell counting kit-8 (CCK-8) was used to detect the effect of different concentrations of Hcy on the survival rate of H9c2 cells to screen the induction concentration and time of Hcy. H9c2 cells were divided into model group, 5 μmol/L Ato group, 10 μmol/L Ato group and 15 μmol/L Ato group, and another normal H9c2 cells were taken as control group. The apoptosis rate was detected by flow cytometry; the change of mitochondrial membrane potential was detected by JC-1 method; the level of intracellular reactive oxygen species (ROS) was measured by DCFH-DA method; enzyme linked immunosorbent assay (ELISA) was used to detect the contents of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT); and the phosphorylation levels of MEK1/2 and ERK1/2 were detected by Western blot. Results Compared with control group, 2 μmol/L Hcy significantly reduced the survival rate of H9c2 cells (P＜0.05), so that, in this study, H9c2 cells were treated with 2 μmol/L Hcy for 24 h. Compared with control group, the apoptosis rate, ROS level and MDA content of H9c2 cells were significantly increased in the model group (P＜0.05), and the mitochondrial membrane potential, SOD, CAT contents and phosphorylation levels of MEK1/2 and ERK1/2 were significantly decreased (P＜0.05). Compared with model group, the apoptosis rate, ROS level and MDA content of H9c2 cells in 5 μmol/L Ato group, 10 μmol/L Ato group and 15 μmol/L Ato group decreased in turn (P＜0.05), and the mitochondrial membrane potential, SOD, CAT contents and phosphorylation levels of MEK1/2 and ERK1/2 increased in turn (P＜0.05). Conclusion Ato may reduce the oxidative stress induced by Hcy in H9c2 cells by activating MEK/ERK pathway and alleviate myocardial mitochondrial damage.