Background: Surgery and postoperative adjuvant therapy is the standard treatment for locally advanced resectable oral squamous cell carcinoma (OSCC), while neoadjuvant chemoimmunotherapy (NACI) is believed to lead to better outcomes. This study aims to investigate the effectiveness of NACI regimens in treating locally advanced resectable OSCC. Materials and methods: Patients diagnosed with locally advanced resectable OSCC who received NACI and non-NACI were reviewed between December 2020 and June 2022 in our single center. The pathologic response was evaluated to the efficacy of NACI treatment. Adverse events apparently related to NACI treatment were graded by Common Terminology Criteria for Adverse Events, version 5.0. The disease-free survival (DFS) and overall survival (OS) rate were assessed. Results: Our analysis involved 104 patients who received NACI. Notably, the pathological complete response rate was 47.1%, and the major pathological response (MPR) rate was 65.4%. The top three grade 1–2 treatment-related adverse events (TRAEs) were alopecia (104; 100%), anemia (81; 77.9%), and pruritus (62; 59.6%). Importantly, patients achieving MPR exhibited higher programmed cell death-ligand 1 (PD-L1) combined positive scores (CPS). The diagnostic value of CPS as a biomarker for NACI efficacy was enhanced when combined with total cholesterol level. The 3-year estimated DFS rates were 89.0% in the NACI cohort compared to 60.8% in the non-NACI cohort, while the 3-year estimated OS rates were 91.3 versus 64.0%, respectively. Conclusions: The NACI treatment showed safe and encouragingly efficacious for locally advanced resectable OSCC patients. The high response rates and favorable prognosis suggest this approach as a potential treatment option. Prospective randomized controlled trials are needed to further validate these findings.