The protective effect of hydrogen sulfide (H2S) against hypoxia-induced injury via anti-apoptosis is well established, but the underlying mechanism remains unclear. The present study aimed to investigate whether miR-455 participated in the H2S protection of lung epithelial cells against CoCl2-induced apoptosis by regulating endoplasmic reticulum stress (ERS)-related genes. Human lung epithelial cells BEAS-2B were subjected to hypoxia injury with or without H2S preconditioning. It was found that hypoxia injury increased apoptosis of BEAS-2B cells, down-regulated the expression of miR-455, and upregulated the expression of calreticulin (Calr). H2S preconditioning attenuated lung epithelial cells apoptosis, enhanced cell viability, up-regulated the expression of miR-455, as well as down-regulated the expression of Calr following hypoxia injury. In addition, Calr, GRP78, C/EBP homologous protein (CHOP) and Caspase-12 protein was down-regulated by the miR-455 mimic and up-regulated by the miR-455 inhibitor. These results implicate miR-455 regulated H2S protection of lung epithelial cells against hypoxia-induced apoptosis by stimulating Calr.