Glaucoma is a group of neurodegenerative diseases characterized by loss of retinal ganglion cells and visual field defects and is one of the major causes of irreversible blindness worldwide. Primary open-angle glaucoma (POAG) is one of the classifications of glaucoma. Oxidative stress in trabecular reticulated cells is one of the possible mechanisms of the development of glaucoma. At present, there is still a lack of effective methods to treat glaucoma. Ghrelin is characterized by its wide distribution and high potency and has anti-inflammatory, antioxidant, and anti-apoptotic effects, which may be beneficial in the treatment of glaucoma. In this study, we investigated whether ghrelin can protect human trabecular meshwork cells (HTMCs) from oxidative damage induced by hydrogen peroxide (HO), as well as the possible mechanism of action. CCK8 and flow cytometry results revealed that treatment of HTMCs with ghrelin showed a dose-dependent protective effect against HO-induced damage. Ghrelin significantly decreased the rate of apoptosis and levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the level of superoxide dismutase (SOD) and catalase (CAT) in HTMCs. The difference was statistically significant compared with the HO group. Ghrelin activated Nrf2/HO-1/NQO-1 signaling pathways and decreased HIF-1α level in HO-injured HTMCs as shown on qPCR and Western blot. In conclusion, ghrelin can protect HTMCs from oxidative damage induced by HO and reduce apoptosis in HTMCs, which can be a new approach to treating POAG. The underlying therapeutic mechanism may be related to Nrf2/HO-1/NQO-1 signaling pathways and HIF-1α.Copyright © 2023. Published by Elsevier Masson SAS.