Background <p>Betel nut chewing (BNC) is a prevalent risk factor for oral squamous cell carcinoma (SCC) in South and Southeast Asia, yet its influence on response to neoadjuvant immunochemotherapy remains unexplored. This study aimed to evaluate the association between BNC and pathologic response in oral SCC patients receiving neoadjuvant immunochemotherapy.</p> Methods <p>We retrospectively reviewed 192 patients with primary oral SCC who received neoadjuvant immunochemotherapy (docetaxel, cisplatin, and PD-1 inhibitors) followed by surgery between January 2020 and October 2024. Pathologic complete response (pCR), major pathologic response (mPR), objective response rate (ORR), clinical to pathological downstaging, adverse pathologic features, and disease-free survival (DFS) were compared between BNC (<i>n</i> = 42) and no-BNC (<i>n</i> = 150) groups.</p> Results <p>BNC patients demonstrated significantly lower pCR (16.7% vs. 34.0%; OR = 2.55, <i>p</i> = 0.031) and mPR rates (54.8% vs. 74.7%; OR = 3.17, <i>p</i> = 0.013) compared to no-BNC patients. Multivariable analysis confirmed absence of BNC as an independent predictor of both pCR (adjusted OR = 2.55, 95% CI: 1.20–7.65) and mPR (adjusted OR = 3.17, 95% CI: 1.32–8.53). BNC was also associated with lower ORR (73.8% vs. 86.7%, <i>p</i> = 0.045), reduced downstaging (71.4% vs. 90.0%, <i>p</i> = 0.002), and higher prevalence of adverse pathologic features (19.0% vs. 4.7%, <i>p</i> = 0.005). The poorest outcomes occurred in well/moderately differentiated tumors with BNC history. BNC did not significantly impact DFS (3-year DFS: 71.2% vs. 78.4%, <i>p</i> = 0.194). Number of neoadjuvant cycles did not influence pathologic response.</p> Conclusions <p>BNC is an independent predictor of suboptimal pathologic response to neoadjuvant immunochemotherapy in oral SCC, although it does not adversely affect DFS. These findings may inform patient selection and treatment stratification.</p>