The clinical outcome of oral squamous cell carcinoma (OSCC) has not improved in recent years, mainly due to the limited effective targeted therapy that has been applied. Recently, a transcriptional coactivator, YAP, has been shown to have a key regulatory role in malignant progression in multiple cancers, including OSCC. But pharmacologically targeting YAP or the Hippo pathway, which is the main signaling pathway regulating YAP, has been proven to be challenging. Therefore, uncovering YAP upstream regulators in cancer would identify novel therapeutic targets for treatment of YAP-sustained cancers. Here, we showed that YAP was overactivated in OSCC and that high YAP activity in patients with OSCC was associated with malignant progression and poor survival. We uncovered that GPR39 (a G protein–coupled receptor) was overexpressed in OSCC, that the expression level of GPR39 was correlated with the activity level of YAP, and that the high GPR39 expression was associated with malignant progression and poor survival in patients with OSCC. Moreover, we found that GPR39 regulated YAP through a Gαq/11-RhoA–dependent signaling pathway. Importantly, inhibition of GPR39 resulted in YAP-sustained OSCC growth inhibition. Our findings suggest that GPR39 is a potential therapeutic target for OSCC treatment with itself as a biomarker.