Background/Objectives: Surgical site infection (SSI) significantly impacts patient outcomes in oncologic head and neck surgery with free flap reconstruction. Perioperative antibiotic prophylaxis (PAP) is widely accepted to prevent SSI. Despite decades of research, infection rates often exceed 40%, and controversies remain regarding antibiotic type and duration. While the literature on general head and neck surgery is abundant, it does not fully address the unique challenges of oncologic patients undergoing complex free flap reconstruction in the head and neck region. This review assesses the evidence for PAP in this population and examines concerns related to antimicrobial resistance (AMR). Methods: We conducted a review of clinical trials, systematic reviews, and relevant literature on PAP in oncologic head and neck surgery with free flap reconstruction. Key aspects included antibiotic type, timing, duration, and impact on SSI rates and patient outcomes. General head and neck surgery literature was considered when procedure-specific data were lacking. Results: PAP reduces SSI rates, but clinical practice varies regarding antibiotic choice and duration. Short-term prophylaxis may suffice for some procedures, whereas prolonged regimens are often used despite limited additional benefit. A multidisciplinary approach considering procedure-specific risks and patient factors improves outcomes. The risk of AMR underscores the need for standardized, evidence-based protocols. Significant gaps remain, particularly concerning optimal PAP regimens for free flap reconstruction. Conclusions: PAP is essential for SSI prevention in head and neck oncologic surgery with free flap reconstruction, yet current practices are heterogeneous. Standardized, procedure-specific protocols are needed to optimize prophylaxis, reduce SSI rates, and limit AMR, ultimately improving patient care and outcomes.