This systematic review and meta-analysis aimed to evaluate surgical complications, pathologic responses, and disease progression in patients with head and neck squamous cell carcinoma treated with neoadjuvant chemotherapy or immunotherapy. A comprehensive literature search was conduct across four databases (PubMed, Embase, Cochrane Library, and Scopus) and grey literature sources to identify neoadjuvant therapies in head and neck cancer patients. Only prospective clinical trials were included. The certainty of evidence was appraised using GRADE tool. A total of 12 clinical trials me the inclusion criteria, comprising, six studies on neoadjuvant chemotherapy (Cisplatin and 5-FU) and six on immunotherapy (Nivolumab, Nivolumab plus Ipilimumab, Pembrolizumab) were analyzed. The mean time from drug administration to surgery ranged from 18 to 29 days. The overall surgical complication rate was 32.8%, with the lowest observed in the Pembrolizumab group (9%) and the highest in the Nivolumab plus Ipilimumab group (36.7%). However, risk ratios for surgical complications were not statistically significant for Nivolumab (RR = 1.68, p = 0.078) or chemotherapy (RR = 1.1, p = 0.70). The complete pathologic response (pCR) rate was low (4%), highest in the Cisplatin and 5-FU group (11%). In contrast, the partial pathologic response (pPR) rate reached 58% with Nivolumab plus Ipilimumab. Disease progression after surgery occurred in 19.4%, with the lowest progression rate observed in the Nivolumab plus Ipilimumab group (7.7%). The certainty of evidence was rated as very low for chemotherapy and low for immunotherapy. Combination immunotherapy, particularly Nivolumab with Ipilimumab, demonstrated favorable pPR rates and reduced disease progression but was increased surgical complications. The overall low pCR across all regimen treatments highlight the need for improved therapeutic strategies.