Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 3% of new cancer cases and 3% of all deaths worldwide. Most HNSCC patients are locally advanced (LA) at diagnosis. The combination of radiotherapy (RT), chemotherapy, targeted therapy, and immunotherapy are the primary LA-HNSCC treatment options. Nevertheless, the choice of optimal LA-HNSCC treatment remains controversial. We systematically searched public databases for LA-HNSCC-related studies and assess treatment effectiveness and safety by assessing the objective response rate (ORR), ≥3 adverse events (AEs), overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), local-region control (LRC), and disease-specific survival (DSS). 126 randomized controlled clinical trials (RCTs) were included in this study. We show that concurrent RT with nimotuzumab or conventional concurrent chemo-radiotherapy (CCRT) had significantly better efficacy and long-term survival without increasing AEs than RT alone. Accelerated fractionated radiotherapy (AFRT) showed better efficiency than conventional fractionated RT, although it had higher AEs. In addition, concurrent cetuximab combined with RT failed to show a significant advantage over RT alone.