Aim To investigate the effect of neuregulin-1(NRG-1) on alleviating hypoxia/reoxygenation (H/R) injury of cardiomyocytes through extracellular regulated protein kinase 1/2 (ERK1/2) pathway. Methods Myocardial H9c2 cell lines were cultured and randomly divided into control group treated with DMEM without drugs under conventional conditions, H/R group treated with DMEM without drugs under H/R conditions, NRG-1 group treated with DMEM containing NRG-1 under H/R conditions, and NRG-1+PD group treated with PD98059 containing NRG-1 and ERK1/2 inhibitors under H/R conditions. Then cell proliferation, apoptosis, apoptosis gene, inflammatory index, ERK1/2 were determined.Results The OD₄₉₀ level of H/R group was significantly lower than that of control group, the apoptotic rate, the expression levels of cleaved caspase-8, cleaved caspase-9, cleaved caspase-3, nuclear factor kappa B (NF-κB), ERK1/2 in cells and the contents of tumor necrosis factor alpha (TNF-α), interleukin 1beta (IL-1β), interferon gamma (IFN-γ) in culture medium were significantly higher than those of control group. The OD₄₉₀ level and the expression level of ERK1/2 in cells of NRG-1 group were significantly higher than those of H/R group, and the apoptotic rate, the expression levels of cleaved caspase-8, cleaved caspase-9, cleaved caspase-3, NF-κB in cells and the contents of TNF-α, IL-1β, IFN-γ in culture medium were significantly lower than those of H/R group. The OD₄₉₀ level and the expression level of ERK1/2 in cells of NRG-1+PD group were significantly lower than those of NRG-1 group, and the apoptotic rate, the expression levels of cleaved caspase-8, cleaved caspase-9, cleaved caspase-3, NF-κB in cells and the contents of TNF-α, IL-1β, IFN-γ in culture medium were significantly higher than those of NRG-1 group. Conclusion NRG-1 can alleviate H/R injury of cardiomyocytes by activating ERK1/2 pathway.