This study investigated the gastroprotective effects and possible mechanism of Kangfuxin (KFX), an ethanol extract of Periplaneta americana L. (Dictyoptera; Blattidae), on improving healing quality and preventing recurrence of gastric ulcer. The effects of KFX were investigated in patients treated with endoscopic submucosal dissection (ESD), gastric ulcer animal model, and rat gastric mucosal cells and fibroblasts. Moreover, the relationship between KFX and p38/NF-κB pathway were explored both in vivo and in vitro. In patients, KFX exhibited protective effects against gastric ulcers and resulted in a decrease in the CD3 expression. In vivo animal experiments confirmed that KFX accelerated ulcer healing by promoting neovascularization (increased CD34 expression), suppressing inflammation (decreased interleukin‐1β (IL-1β), myeloperoxidase (MPO), tumor necrosis factor α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and IL-8 expression), and enhancing growth factor expression, including the epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF). In vitro experiments demonstrated that treatment with 10% KFX rat serum decreased IL-1β, IL-1Ra, SIL-1RAP, TNF-α, and ICAM-1 expression in rat gastric mucosal cells or fibroblasts and increased IL-1R expression compared to that in the group treatment with 10% normal rat serum. Furthermore, KFX inhibited the activation of p38/NF-κB pathway both in vivo and in vitro. In conclusion, KFX treatment could effectively improve healing quality and prevent gastric ulcer recurrence, which might be attributed to neovascularization, suppressed inflammation, and enhanced growth factor expression. The p38/NF-κB pathway may be one of important mechanism to mediate the effects of KFX.