Cuttlebone complex (CBC), a homology of medicine and food formula, is comprised of five herbal medicines (Endoconcha Sepiae, Radix Paeoniae Rubra, fresh ginger, Fructus Amomi, and Radix Glycyrrhizae) and two food ingredients (Zingiber zerumbet and chitosan). Herein, the gastroprotective potential against indomethacin and a safety assessment of CBC were investigated. In a gastroprotective model, CBC effectively decreased the indomethacin-increased gastric ulcerous lesions, and increased the indomethacin-decreased prostaglandin E2 levels in the gastric mucosa. In genotoxicity tests, CBC treatment did not increase the numbers of revertant colonies in five Salmonella typhimurium strains and chromosome aberrations in Chinese hamster ovary CHO-K1 cells, with or without S9 metabolic activation. The oral supplementation of CBC did not increase micronucleus formation in the peripheral blood of mice. In a subacute toxicity study, the body weight and blood biochemical parameters observed in CBC-treated rats were normal. In conclusion, CBC was considered as a non-toxic formula and could be used to remedy indomethacin-induced gastric damage.