"Background: In this study, we aimed to investigate the potential of miR-19a as a biomarker of OSCC and its underlying molecular mechanisms. Methods: We collected serum and saliva samples from 66 OSCC patients and 66 healthy control subjects. Real-time PCR analysis, bioinformatic analysis and luciferase assays were performed to establish a potential signaling pathway of miR-19a/GRK6/GPCRs/PKC. Flowcytometry and Transwell assays were performed to observe the changes in cell apoptosis, metastasis and invasion. Results: We found that miR-19a, GPR39 mRNA and PKC mRNA were upregulated while GRK6 mRNA was downregulated in the serum and saliva samples collected from OSCC patients. Moreover, in silico analysis confirmed a potential binding site of miR-19a on the 3'UTR of GRK6 mRNA, and the subsequent luciferase assays confirmed the molecular binding between GRK6 and miR-19a. We further identified that the over-expression of miR-19a could regulate the signaling between GRK6, GPR39 and PKC via the signaling pathway of miR-19a/GRK6/GPR39/PKC, which accordingly resulted in suppressed cell apoptosis and promoted cell migration and invasion. Conclusion: Collectively, the findings of our study propose that miR-19a is a crucial mediator in the advancement of OSCC, offering a potential avenue for the development of innovative therapeutic interventions aimed at regulating GRK6 and its downstream signaling pathways."