Chemical therapeutics targeted against H. pylori may lead to host toxicity and pathogen eradication failures. In this study, ethanolic extracts from five Lespedeza sp. plants were shown to inhibit the gastric-pathogen H. pylori and to modulate cytokine production. Disc agar diffusion assays showed that Lespedeza sp. ethanol extracts possess potent anti-H. pylori activity. Among the five plant extracts, the extracts from L. cyrtobotrya demonstrated the highest anti-H. pylori effect. The growth inhibitory effect against H. pylori was initiated after six h of treatment with plant extracts and the effect remained for a continuous period of 48 h. Incubation of the gastric cells infected with H. pylori with 1.25 to 50 mg/mL of Lespedeza sp. plant extracts resulted in a reduction of the production of cytokine IL-8. The plant ethanol extracts generally had little influence on AGS cell viability, indicating their safety for the treatment of bacterial infections. Three active fractions of L. cyrtobotrya also demonstrated similar anti-H. pylori and immuno-modulatory effects. Taken together, these results provide evidence that Lespedeza sp. plant extracts might be potential sources of new host friendly anti-H. pylori agents.