The continuing use of nonsteroidal anti-inflammatory drugs (NSAIDs) usually increases the side effects such as peptic ulcer and acute gastric lesions in the gastrointestinal tract. Cuttlebone (CB), isolated from Sepiella maindroni de Rochebrune, was reported to have antioxidant activities, but its role in the treatment of indomethacin-induced gastric lesions has not yet been confirmed. In this research, we investigate the protective effect of cuttlebone on indomethacin-related ulcers in rats and possible mechanisms. Here, gastric ulcers were induced by oral administration of indomethacin, and then the rats were treated with omeprazole (4 mg/kg) or different doses (750, 1500, and 3000 mg/kg of body weight) of cuttlebone. We evaluated lesion index, inflammation score, and a series of oxidant/antioxidant parameters. The data demonstrated that cuttlebone could protect against gastric ulcers induced by indomethacin in a dose-dependent manner (positive correlation). Also, these effects were associated with attenuating the expression of malonaldehyde (MDA) and increasing the levels of some protective ingredients like epidermal growth factor (EGF), prostaglandin E2 (PGE2), and superoxide dismutase (SOD). Thus, considering its ability to protect indomethacin-induced acute gastric mucosal lesions and the underlying mechanisms, CB might be a potential candidate for treating gastric damage caused by NSAIDs.