Oral squamous cell carcinoma (OSCC) remains a major global health challenge due to its high recurrence rate and poor prognosis. Perineural invasion (PNI), characterized by tumor cells infiltrating nerves, has been frequently reported in OSCC; however, its precise prognostic significance remains debated. To comprehensively clarify this, we performed a systematic review and meta-analysis assessing the prognostic impact of PNI on clinical outcomes in OSCC. Relevant studies published between 2015 and 2025 were systematically searched and selected, extracting hazard ratios (HR) for overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and local recurrence (LR) from multivariate analyses. Fifty-seven eligible studies, encompassing 23,580 patients, were included. Meta-analysis demonstrated that the presence of PNI significantly correlated with worse OS (HR = 1.67; 95% CI: 1.49–1.87), DFS (HR = 1.71; 95% CI: 1.59–1.84), DSS (HR = 1.52; 95% CI: 1.35–1.72), and increased risk of LR (HR = 2.68; 95% CI: 1.70–4.24). Subgroup and sensitivity analyses confirmed robust and consistent prognostic associations, despite moderate publication bias in OS, DFS, and DSS outcomes. These findings provide strong evidence that PNI independently predicts adverse clinical outcomes in OSCC. Our results underscore the critical importance of incorporating PNI status into clinical risk stratification, guiding decisions on surgical management and adjuvant therapies. Future studies should focus on standardizing diagnostic methods and further elucidating underlying molecular mechanisms to optimize patient care.