Helicobacter pylori is a Gram-negative bacterium that is the major cause of many upper gastrointestinal diseases such as gastritis and peptic ulcer disease. It has the unique ability of colonising the human gastric mucosa. Failure in complete eradication of H. pylori in infected patients, mainly due to antibiotic resistance, has necessitated the development of better therapeutics, especially from natural sources.In this study, extract of Maris piper potatoes were obtained and evaluated for antibacterial activity against H. pylori in vitro. Antibacterial activity was carried out against antibiotic-sensitive and clinical antibiotic-resistant H. pylori strains, as well as a range of Gram-negative bacteria including Helicobacter and Campylobacter species, using the viable count method. Result of the antibacterial assays indicated that potato extract is bactericidal against H. pylori lab strain as well as clinical antibiotic-resistant strains, with minimum inhibitory concentration at 15.6 mg/ml. Potato extract also showed minimal antibacterial activity against other Gram- negative bacteria tested, with minimum inhibitory concentration at 250 mg/ml. The effect of the extract on the morphology of H. pylori was also observed by transmission electron microscopy (TEM). TEM analysis of potato extract-treated H. pylori cells showed disruption of the morphology of H. pylori, characterized by separation of the outer membrane from the inner membrane and loss of cell shape. Potato extract also caused hyperpolarisation of H. pylori plasma membrane; however it is unclear whether the membrane active pumping activity is affected.Mutants of H. pylori that are resistant to potato extract were generated as a means to identify the target of potato extract within the H. pylori genome. Genome sequence analysis led to the discovery of a hypothetical protein, encoded by HP0603 gene, which may be involved in inducing resistance to potato extract.The results obtained in this study provide great insights into the anti-H. pylori activity of potato extract. Overall, this study suggests the potential use of potato extract as a source of anti-H. pylori agents; and stimulates further studies into identifying its mechanism of action.