Despite improvements in therapeutic approaches, the mortality rate of gastric cancer (GC) remains unacceptably high. Evidence suggests that FXYD domain containing ion transport regulator 6 (FXYD6) is downregulated in GC. However, its exact function and the molecular mechanism in GC are still unclear. FXYD6 expression in different cell lines was estimated using RT-qPCR. Western blotting was employed for protein expression detection. Cell counting kit-8 assay, colony formation assay, and flow cytometry were implemented to assess GC cell viability, proliferation, and apoptosis, respectively. Bioinformatics analysis as well as chromatin immunoprecipitation and luciferase reporter assays were utilized for verifying FXYD6 interaction with the transcription factor Krüppel-like factor 10 (KLF10). The results showed that FXYD6 displayed a decreased level in GC cell lines. Impaired proliferative ability and enhanced apoptotic capacity were observed in GC cells overexpressing FXYD6. KLF10 expression is positively correlated with FXYD6 expression in GC samples. KLF10 binds to the FXYD6 promoter to enhance its transcription. FXYD6 depletion counteracted KLF10 upregulation-triggered reduction in GC cell proliferation and elevation in apoptosis. In conclusion, KLF10 activates FXYD6 transcription, thereby impeding GC cell proliferation and promoting cell apoptosis.