It was previously confirmed that hydrogen sulfide (H2S) has a neuroprotective effect, preventing homocysteine‑induced neurotoxicity. However, the exact molecular mechanisms underlying this protective effect remain to be fully elucidated. Endoplasmic reticulum (ER) stress contributes to homocysteine‑induced neurotoxicity. Silent mating type information regulator 2 homolog 1 (SIRT‑1) can attenuate ER stress, exerting its neuroprotective effect. Therefore, the present study aimed to investigate whether H2S protects PC12 cells against homocysteine‑induced ER stress and whether SIRT‑1 mediates this protective effect of H2S. Western blotting was used to detect the expression of SIRT‑1, glucose‑regulated protein 78 (GRP78), and cleaved caspase‑12 in PC12 cells. It was observed that sodium hydrosulfide (NaHS), an exogenous H2S donor, significantly attenuated the homocysteine‑induced ER stress responses, including increases in the protein expression levels of GRP78 and cleaved caspase‑12. Simultaneously, NaHS upregulated the expression of SIRT‑1 and reversed the homocysteine‑induced downregulation of SIRT‑1 in PC12 cells. Sirtinol, a specific inhibitor of SIRT‑1, eliminated the protective effects of H2S in homocysteine‑induced ER stress. These data indicated that H2S prevented homocysteine‑induced ER stress via enhancing the expression of SIRT‑1. These findings offer novel insight into the protective mechanisms of H2S against homocysteine‑induced neurotoxicity.