Natural products are sources for exploratory development of new agents to combat the gastric pathogen Helicobacter pylori. Some edible fungi, such as the lion's mane mushroom, have been used for several thousand years to treat digestive diseases. Ethanol-based extractions to prepare Hericium erinaceus extracts were tested for growth inhibition ability of six different H. pylori strains at an extract concentration that did not inhibit Escherichia coli growth, and further for dose-dependent antibactericidal capacity on H. pylori. H. erinaceus extract exhibited similar growth inhibitory effects on all H. pylori strains tested, with a minimum inhibitory concentration of about 2 mg/mL. H. pylori survival in phosphate-buffered saline (PBS) was decreased 3 logs by 2 mg/mL extract addition. H. erinaceus extract inhibited H. pylori adhesion capacity to human gastric epithelial cell line (ATCC CRL-1739) (AGS), even when H. erinaceus extract was added at a concentration that affected neither H. pylori nor AGS viability. Interleukin-8 (IL-8, representing an immune response factor) in supernatants from AGS and 8-oxo-guanine (8-oxoG, a marker for oxidative DNA damage among the total host cell DNA) were measured from AGS cells exposed to H. erinaceus extract before H. pylori addition. The subsequent H. pylori-mediated immune response (IL-8 production) was significantly (P < 0.01) decreased by H. erinaceus extract; at 1.0 mg/mL extract addition, IL-8 expression returned to nearly background level (no H. pylori added). H. pylori infection of AGS caused a 3-fold increase in host 8-oxoG, but this increase was abolished by including 2 mg/mL H. erinaceus extract. Mouse colonization assays of C57BL mice were performed on homogenized stomachs 3 weeks after inoculating H. pylori into the animals; mice receiving the H. erinaceus extract had a mean H. pylori load of 6 × 104 CFU/g of stomach, about 1 log lower than the control (no extract) animals.