miRNAs have been pointed to play critical roles in the protection and development of cyanotic congenital heart disease (CHD). MiR-182 is found to be associated with multiple heart diseases. However, little is known about the function and underlying mechanisms of miR-182 on cyanotic CHD. Here, H9c2 cells were exposed to hypoxia to construct the model of cyanotic CHD in vitro. qRT-PCR assay revealed that miR-182 expression was downregulated in serum samples from patients with cyanotic CHD and hypoxia-induced cardiomyocytes. Gain- and loss-of-function demonstrated that miR-182 overexpression promoted cell proliferation and suppressed apoptosis in hypoxia-induced H9c2 cells, while miR-182 knockdown repressed cell proliferation and promoted apoptosis. Dual-luciferase reporter assay verified that HES1 was a direct target of miR-182, and miR-182 repressed HES1 expression by binding to its 3′-UTR. Moreover, miR-182-mediated regulatory effect on cell proliferation and apoptosis was reversed by the restoration of HES1 expression. In conclusion, our study demonstrated that miR-182 exerted protection effect through suppressing HES1 in hypoxia-induced cardiomyocytes, highlighting its role as a potential therapeutic strategy for cyanotic CHD.