The emergence of antibiotic-resistant Helicobacter pylori strains impacts the efficacy of eradication therapy and promotes the development of alternative treatment strategies. Apocynin inhibits neutrophil NADPH oxidase and hence may decrease reactive oxygen species-mediated tissue damage in H. pylori-infected stomach tissue. Apocynin was tested in vitro for its cytotoxic and direct antibacterial effects. The therapeutic efficacy of orally administered apocynin (100 mg/kg/day through drinking water or 200 mg/kg/day through combined administration of drinking water and slow-release formulation) was assessed at 9 weeks after infection in the Mongolian gerbil model. Bacterial burdens were quantified by viable plate count and quantitative PCR. Histopathological evaluation of antrum and pylorus provided insight into mucosal inflammation and injury. Apocynin showed no cytotoxic or direct antibacterial effects in vitro or in vivo. Nine weeks of apocynin treatment at 200 mg/kg/day reduced active H. pylori gastritis as neutrophil infiltration in the mucous neck region and pit abscess formation decreased significantly. In our gerbil model, prolonged high-dose apocynin treatment significantly improved H. pylori-induced pit abscess formation without indications of drug toxicity and thus further investigation of the dosage regimen and formulation and the long-term impact on neoplastic development should be carried out.