Gastric cancer remains one of the most common deadly diseases and lacks effective targeted therapies. In the present study, we confirmed that the signal transducer and activator of transcription 3 (STAT3) is highly expressed and associated with a poor prognosis in gastric cancer. We further identified a novel natural product inhibitor of STAT3, termed XYA-2, which interacts specifically with the SH2 domain of STAT3 (K_d = 3.29?μM) and inhibits IL-6-induced STAT3 phosphorylation at Tyr705 and nuclear translocation. XYA-2 inhibited the viability of seven human gastric cancer cell lines with 72-h IC₅₀ values ranging from 0.5 to 0.7 μΜ. XYA-2 at 1 μΜ inhibited the colony formation and migration ability of MGC803 (72.6% and 67.6%, respectively) and MKN28 (78.5% and 96.6%, respectively) cells. In the in vivo studies, intraperitoneal administration of XYA-2 (10?mg/kg/day, 7 days/week) significantly suppressed 59.8% and 88.8% tumor growth in the MKN28-derived xenograft mouse model and MGC803-derived orthotopic mouse model, respectively. Similar results were obtained in a patient-derived xenograft (PDX) mouse model. Moreover, XYA-2 treatment extended the survival of mice bearing PDX tumors. The molecular mechanism studies based on transcriptomics and proteomics analyses indicated that XYA-2 might exert its anticancer activity by synergistically inhibiting the expression of MYC and SLC39A10, two downstream genes of STAT3 in vitro and in vivo. Together, these findings suggested that XYA-2 may be a potent STAT3 inhibitor for treating gastric cancer, and dual inhibition of MYC and SLC39A10 may be an effective therapeutic strategy for STAT3-activated cancer.