Long-term excessive alcohol intake can directly injure the gastroduodenal mucosa, causing gastric erosions, gastric ulcers, and gastrorrhagia. Fritillaria ussuriensis Maxim is a famous traditional Chinese medicine and health food produced in China. Sipeimine is an alkaloidal component of Fritillaria ussuriensis Maxim. This research aimed to investigate the protective effects of sipeimine on ethanol-induced gastric ulcers in mice. The results displayed that sipeimine could alleviate gastric tissue damage and decrease the levels of SOD, MDA, IL-6, IFN-γ, TNF-α, and IL-1β. Sipeimine treatment also adjusted macrophage polarization and the balance of Th17/Treg cell by reducing the expression of Jak1/2, p-Jak1/2, Stat1/3, and p-Stat1/3. Moreover, sipeimine could increase the abundance of Lactobacillus_johnsonii and decrease the abundance of Bacteroides_vulgatus in the gut microbiota. Meanwhile, sipeimine treatment significantly decreased the abundance of Rodentibacter_heylii and Streptococcus_cuniculi in the gastric microbiota. In conclusion, sipeimine can improve gastric ulcers by suppressing the Jak-Stat pathway, reversing gut-gastro microbiota dysbiosis, inhibiting macrophage M1 polarization, maintaining the balance of Th17/Treg cell, and lessening sustained inflammatory injury.