Objectives <p>Neoadjuvant therapy has been increasingly explored as a treatment strategy for oral squamous cell carcinoma (OSCC) and may be associated with favorable pathological responses. However, its long-term efficacy and safety have not yet been systematically evaluated. Therefore, this study aimed to comprehensively synthesize the available evidence regarding the clinical outcomes of neoadjuvant therapy in patients with OSCC.</p> Methods <p>We systematically searched three electronic databases (PubMed, Embase, and the Cochrane Library) for relevant studies evaluating neoadjuvant therapy in OSCC. Eligible studies published up to June 1, 2025 were included. A random-effects meta-analysis was performed to estimate pooled proportions of disease-free survival (DFS) and overall survival (OS). Safety outcomes were assessed based on the incidence of grade 3 or higher treatment-related adverse events (TRAEs). Data extraction and quality assessment were independently performed by two reviewers in accordance with the PRISMA guidelines.</p> Results <p>A total of ten studies involving 578 patients met the eligibility criteria and were included in the analysis. The pooled DFS rates at 12 and 24 months were 68% and 41%, respectively. Correspondingly, the pooled OS rates were 83% at 12 months and 52% at 24 months. The pooled incidence of grade 3–4 treatment-related adverse events was 19%.</p> Conclusions <p>Neoadjuvant therapy demonstrates encouraging efficacy and an acceptable safety profile in patients with OSCC. Nevertheless, further high-quality studies with longer follow-up periods are required to confirm these findings.</p>