A meta-analysis examination was implemented to review the effect of Clindamycin compared with Ampicillin-Sulbactam as prophylactic antibiotics (PAs) management for surgical site wound infections (SSWIs) following major surgery (MS) for head and neck cancer (H&NC). A comprehensive literature examination till May 2023 was done and 1296 interrelated examinations were reviewed. The six elected examinations, enclosed 4293 personals with MS for H&NC were in the utilized examinations' starting point, 1722 of them were utilizing Clindamycin, and 2571 were utilizing Ampicillin-Sulbactam. Odds ratio (OR) and 95% confidence intervals (CIs) were utilized to appraise the consequence of Clindamycin compared with Ampicillin-Sulbactam as PAs management for SSWIs following MS for H&NC by the dichotomous approach and a fixed or random model. Clindamycin had significantly higher SSWI compared with Ampicillin-Sulbactam (OR, 2.65; 95% CI, 1.40–5.02, p = 0.003) in personals with MS for H&NC. Clindamycin had significantly higher SSWI compared with Ampicillin-Sulbactam in personals with MS for H&NC. However, caution needs to be taken when interacting with its values because there was a low sample size of some of the chosen examinations and a low number of examinations found for the comparisons in the meta-analysis.