Increasing study has suggested that microRNAs (miRNAs) are pivotal regulators in regulating hypoxia-induced injury. miR-142-5p has been suggested as a critical regulator for cellular survival. However, the role of miR-142-5p in regulating hypoxia-induced injury remains unknown. In this study, we aimed to investigate the mechanistic roles of miR-142-5p in regulating cell survival during hypoxia treatment using H9C2 cardiomyoblasts and primary cardiomyocytes. We showed that miR-142-5p expression level was significantly repressed by hypoxia treatment. Overexpression of miR-142-5p during hypoxia induced extensive cell injury and apoptosis whereas suppression of miR-142-5p significantly promoted cell viability and attenuated cell apoptosis with hypoxia treatment. Sirtuin7 (SIRT7) was identified as a direct target gene of miR-142-5p by bioinformatics analysis and dual-luciferase reporter assays. Overexpression of miR-142-5p significantly decreased SIRT7 expression, while suppression of miR-142-5p increased SIRT7 expression. Furthermore, overexpression of SIRT7 protected H9C2 cardiomyoblasts and primary cardiomyocytes against hypoxia-induced injury and apoptosis. The silencing of SIRT7 markedly abrogated the protective effect induced by miR-142-5p suppression. Taken together, these results suggest that downregulation of miR-142-5p alleviates hypoxia-induced injury through upregulation of SIRT7. Our study suggests miR-142-5p/SIRT7 as potential therapeutic targets for ischemic heart disease.