Abstract: Objective: To evaluate the protective effects of the combined use of fucoidan and sodium alginate against acute gastric mucosal injury induced by absolute ethanol in rats, and to investigate the underlying mechanisms involved. Methods: Male SD rats were selected as the experimental subjects and randomly divided into seven groups: A blank control group, a model group, a fucoidan group (0.3 g/kg), a sodium alginate group (0.3 g/kg), a low-dose combination group (fucoidan:sodium alginate=5:3, 0.3 g/kg), a medium-dose combination group (0.6 g/kg), and a high-dose combination group (1.2 g/kg). The rats received the corresponding treatments once daily for 30 days. The protective effects of the combined treatment against ethanol-induced acute gastric mucosal injury were assessed through gastric mucosal injury scoring and histopathological examination. Additionally, enzyme-linked immunosorbent assay (ELISA) and colorimetric assays were employed to measure the levels of inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), oxidative stress marker malondialdehyde (MDA), antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), as well as gastric mucosal protective factors prostaglandin E2 (PGE-2) and nitric oxide (NO) to explore the potential mechanisms. Results: The results indicated that, compared to the model group, the gastric mucosal injury index and histopathological scores were significantly reduced in the low, medium, and high-dose combination groups after treatment with fucoidan and sodium alginate (P<0.001), with injury inhibition rates of 45.74%, 49.87%, and 59.19%, respectively. Histological staining of gastric tissues revealed that the combined treatment provided significant protection against acute gastric mucosal injury from a morphological and histopathological perspective. Furthermore, all three dosage groups of the combined treatment significantly decreased the levels of IL-6 and MDA in gastric tissues (P<0.05, P<0.01, P<0.001) while significantly increasing the activities of SOD and CAT, as well as the level of PGE-2 (P<0.01, P<0.001). Notably, only the high-dose group significantly reduced the level of TNF-α in gastric tissues (P<0.05), and both the medium and high-dose groups significantly increased the level of NO (P<0.05, P<0.001). In contrast, when administered separately, fucoidan and sodium alginate only had a significant effect on MDA levels in gastric tissues (P<0.001). Compared to the individual treatments, the combination showed a more pronounced synergistic effect, demonstrating the rationale for their combined use. Moreover, the combined treatment exhibited a more pronounced synergistic effect compared to the individual administration of fucoidan or sodium alginate, supporting the rationale for their combination. Conclusion: The combined use of fucoidan and sodium alginate exhibits significant protective effects against ethanol-induced acute gastric mucosal injury in rats, with potential mechanisms primarily involving anti-inflammatory, antioxidant, and gastric mucosal protective pathways.