OBJECTIVE: Oral squamous cell carcinoma (OSCC) is a prevalent cancer of the head and neck region. However, the potential role of RCN2 in OSCC is currently not well understood. STUDY DESIGN: A series of molecular biology experiments were conducted to explore the mechanism by which RCN2 promotes OSCC growth through protein kinase A (PKA). RESULTS: Our results revealed a significant increase in RCN2 levels in OSCC tissues. Moreover, OSCC patients with high RCN2 expression had a significantly worse prognosis than those with lower RCN2 expression. Interestingly, PKA activity was increased in RCN2-overexpressing YD-10B cells but reduced in RCN2-knockout Ca9-22 cells. These findings suggest that RCN2-mediated PKA activity is activated in OSCC cells. Moreover, the specific PKA inhibitor H89 significantly reduced the proliferation ability of RCN2-overexpressing Ca9-22 cells. Furthermore, we identified AKT/mTORC as a downstream pathway through which PKA promotes OSCC cell proliferation. The Tumor Immune Estimation Resource database revealed that the expression level of RCN2 was correlated with the infiltration levels of B cells, CD8+ T cells, CD4+ T cells, and neutrophils in the microenvironment of OSCC. CONCLUSIONS: Our study revealed that RCN2 promotes tumor progression by activating PKA/AKT/mTORC signaling, which suggests that RCN2 may serve as a potential target for OSCC treatment.