Infection in orthopedic surgery is a highly feared and undesirable consequence. It is linked to long-lasting illness, impairment, and higher death rates. Surgical site infection in clean wounds, specifically closed uninfected wounds, include both incisional and organ space infections.1 Of the approximately 30 million surgeries performed in the United States annually, about 2% are accompanied by surgical site infections. Prophylactic antibiotics have a well-established function in decreasing the occurrence of surgical site infections (SSIs) in orthopedic surgery. Their effectiveness is shown by strong clinical data, and their appropriate use is essential to surgical practice. Following criteria for the time, selection, and duration of antibiotic administration may greatly increase the results of surgical procedures, save healthcare expenses, and improve patient safety. Aim: To examine the existing literature on the use of surgical antibiotic prophylaxis in orthopedic surgery and explore the potential consequences associated with the inappropriate administration of antibiotics. Materials and method: A systematic review was conducted during June 2020 to April 2021 using the MeSH Terms)antibiotics in orthopaedic, drugs in orthopaedic surgery, prophylactic antibiotics in orthopaedics. Pubmed, Scopus, Embase and google scholar databases were also searched with the same search strategy and the references of selected journals were scanned to try to find more studies. Conclusion: Prophylactic antibiotics are a cornerstone of infection prevention in orthopedic surgery. Their use significantly reduces the risk of surgical site infections, leading to better patient outcomes and reduced healthcare costs. The choice and timing of antibiotic administration are critical factors in maximizing their effectiveness. While the benefits of prophylactic antibiotics are well established, it is essential to balance these benefits against the risks of antibiotic resistance and adverse effects. Adhering to current guidelines and exploring innovative approaches, such as antibiotic-coated implants and decolonization strategies, will help ensure the continued success of prophylactic antibiotics in orthopedic surgery.