Taking palmatine (PMT) as the lead, 20 new PMT derivatives were synthesized and examined for their antibacterial activities against six tested metronidazole (MTZ)‐resistant Helicobacter pylori (H. pylori) strains. The structure-activity relationship (SAR) indicated that the introduction of a suitable secondary amine substituent at the 9‐position might be beneficial for potency. Among them, compound 1c exhibited the most potent activities against MTZ‐resistant strains, with minimum inhibitory concentration (MIC) values of 4-16 μg/mL, better than that of the lead. It also exhibited a good safety profile with a half‐lethal dose (LD50) of over 1000 mg/kg. Meanwhile, 1c might exert its antimicrobial activity through targeting H. pylori urease. These results suggested that PMT derivatives might be a new family of anti‐H. pylori components. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).