Jatrorrhizine (JATR), a natural isoquinoline alkaloid from Coptidis Rhizoma, exhibits various pharmacological activities, including antibacterial, anti-inflammatory, and antitumor effects. While JATR is known to treat chronic gastritis, its therapeutic potential for chronic atrophic gastritis (CAG) and its underlying mechanisms are not fully understood. This study induced CAG in rats using N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 12 weeks through free drinking and force-feeding. Serological metabolomics identified 23 core targets of JATR related to CAG improvement. Reverse transcription-quantitative polymerase chain reaction and western blotting confirmed the involvement of these targets. Molecular docking revealed interactions between JATR and IL-1β and Caspase-3. JATR significantly alleviated gastric inflammation and atrophy, with Kyoto Encyclopedia of Genes and Genomes analysis showing enrichment in the "Nod-like receptor-related pyroptosis pathway". JATR also enhanced GES-1 cell proliferation and reduced MNNG-induced cell damage. Additionally, JATR downregulated pyroptosis-related (Gasdermin D, NLRP3, Caspase-1) and apoptosis-related (Bcl-2, Bax, Caspase-3) markers. These findings suggest that JATR may ameliorate MNNG-induced CAG by inhibiting the activation of the Nod-like receptor-related pyroptosis pathway, supporting its potential as a therapeutic intervention for CAG.