Gastric cancer (GC) is one of the most common malignant tumors and recent data demonstrates the tumor suppressor role of VGLL4 in GC, but the mechanisms for VGLL4 downregulation in GC remain to be elucidated. Here, we confirmed the suppressor role of VGLL4 on proliferation and invasion in GC cells with over-activated YAP-TEAD signal, and indicated the reverse correlation between expression patters of VGLL4 and miR-222. Bioinformatics analysis combined with experimental confirmation revealed VGLL4 is a direct target of miR-222 in GC cells. Functionally, miR-222 inhibitor significantly inhibited GC cells proliferation and invasion and VGLL4 knockdown abolished the effects of miR-222 inhibitor. Moreover, TEAD1 knockdown resulted in decrease of miR-222 expression and increase of VGLL4 expression, and also resulted in reduction of luciferase activity driven by miR-222 promoter in GC cells, suggesting over-activated TEAD1 positively feedback transcriptionally regulates miR-222 expression via physically binding to the miR-222 promoter indicated by ChIP assay. Collectively, our findings implied the important role of miR-222/VGLL4/YAP-TEAD1 regulatory loop maintaining over-activated YAP-TEAD1 signal in GC cells, and enriched the rationale of VGLL4 in GC based on which a promising therapeutic strategy will be developed.