The study was to investigate the protective effect of total flavonoid from Ba lotus leaf (BLLF) on reserpine (10 mg/kg)-induced gastric ulcer in KM (Kunming) mice. BLLF was given by gavage in mice, the serum and gastric tissue levels of MOT, SP, VIP, SS, SOD (T-SOD), GSH-Px and MDA were tested by experiment kits, the cytokine levels of TNF-α, IFN-γ, IL-6, and IL-12 were also checked by kits. The mRNA expression in gastric tissue was measured by RT-PCR assay. BLLF significantly reduced reserpine-induced gastric juice secretion and increased the pH of gastric juice. BLLF treatment also increased the levels of VIP and SS and reduced MOT, SP and inflammatory cytokines in serum. In addition, BLLF treatment was able to increase the gastric T-SOD, GSH-Px and reduced the MDA productions in gastric ulcer mice. It also modulated the gastric expression of NF-κB, IκB-α, Mn-SOD, Cu/Zn-SOD, GSH-Px, EGF and EGFR in ulcer mice by RT-PCR assay. These results propound that BLLF exhibits a protective effect against reserpine-induced gastric ulcers in KM mice by reducing gastric juice secretion, modulating serum neuropeptide levels, attenuating serum inflammatory cytokines, increased the gastric antioxidant activity and regulating gastric levels of NF-κB, IκB-α, EGF and EGFR.