Surgical site infections (SSIs) remain a significant concern in the field of surgery, contributing to patient morbidity, prolonged hospital stays, and increased healthcare costs. Antibiotic prophylaxis, the administration of antibiotics before surgery, has been a cornerstone in preventing SSIs for decades. This review explores the current state of antibiotic prophylaxis in surgery, offering insights into its effectiveness, challenges, and emerging trends. In this comprehensive analysis, we delve into the historical development of antibiotic prophylaxis, examining its evolution from early practices to modern guidelines. We explore the various classes of antibiotics commonly used, their dosing regimens, and the importance of timing in optimizing prophylactic interventions. Additionally, we investigate the role of patient-specific factors, such as comorbidities and allergies, in tailoring antibiotic prophylaxis to individual needs. While antibiotic prophylaxis has undeniably reduced the incidence of SSIs, concerns about antimicrobial resistance and adverse effects necessitate a reevaluation of current practices. This review presents a critical assessment of the challenges posed by the overuse and misuse of antibiotics in surgery and highlights the urgent need for judicious antibiotic stewardship. Moreover, the future of antibiotic prophylaxis holds promise with the emergence of innovative strategies such as antimicrobial coatings, probiotics, and immunomodulatory agents. We discuss these novel approaches and their potential to enhance SSI prevention while minimizing antibiotic-related risks. In conclusion, antibiotic prophylaxis in surgery has been instrumental in reducing SSIs, but its continued effectiveness requires a multifaceted approach. By addressing current challenges, promoting antibiotic stewardship, and embracing innovative strategies, we can advance the field of SSI prevention and improve patient outcomes in the years to come. This review provides valuable insights and direction for clinicians, researchers, and policymakers as they navigate the evolving landscape of surgical prophylaxis.