Objective To compare the efficacy and safety of different neoadjuvant treatment options in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Method We conducted a comprehensive literature search across four major databases (PubMed, Web of Science [WOS], Embase, and Cochrane Library) from their inception through August 2024. The primary outcome measures included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and serious adverse events (SAEs). Result This analysis included 23 studies (19 randomized controlled trials [RCTs] and 3 non-RCTs) involving 4,052 patients. Network meta-analysis (NMA) revealed the following findings: Regarding efficacy, thermochemotherapy demonstrated superior outcomes in both objective response rate (ORR) and overall survival (OS), followed by immunochemotherapy. Thermochemotherapy showed significantly better ORR compared to targeted therapy + chemotherapy, TP, PF, T, and single-agent immunotherapy ( P < 0.05). Similarly, immunochemotherapy outperformed all other therapies except thermochemotherapy in ORR (P < 0.05). For OS, both thermochemotherapy and TPF were significantly more effective than PF and TP ( P < 0.05). In progression-free survival (PFS), immunochemotherapy showed the best results, followed by targeted therapy plus chemotherapy, with immunochemotherapy being significantly superior to PF ( P < 0.05). Regarding safety, thermochemotherapy showed the poorest safety profile, followed by TPF. Specifically, T and TP demonstrated significantly better safety than thermochemotherapy ( P < 0.05). Conclusion In the neoadjuvant treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), both thermochemotherapy and immunochemotherapy regimens have demonstrated promising therapeutic efficacy; however, their safety profiles require further comprehensive evaluation. Register:PROSPERO CRD42024571174