Aim: The aim of this study was to compare the efficacy of single-dose prophylactic antibiotics versus empirical post-operative antibiotic regimens in the prevention of surgical site infections (SSIs) among patients undergoing elective surgeries. Materials and Methods: The study was conducted during March 2022 to September 2022 at Jawaharlal Nehru Medical College & Hospital, Bhagalpur, Bihar, India. This was a prospective, randomized comparative study conducted on 160 patients who were undergoing elective surgeries. Patients were divided into two groups: Group A (n=80) received a single-dose prophylactic antibiotic 30-60 minutes before the surgical incision, while Group B (n=80) received post-operative antibiotics for 5 days. SSIs were monitored for 30 days post-operatively, and outcomes were assessed through clinical examination and microbiological testing. Results: The overall incidence of SSIs was higher in Group B (12.5%) compared to Group A (7.5%), though this difference was not statistically significant. Superficial SSIs were more common in Group B (7.5%) than in Group A (5%), while deep SSIs occurred in 3.75% of Group B and 1.25% of Group A. Group A showed better wound healing outcomes, with 90% of wounds healing normally compared to 82.5% in Group B. Additionally, patients in Group B had longer hospital stays and required more days for recovery. Antibiotic non-compliance was significantly higher in Group B (8.75%) compared to Group A (1.25%). Conclusion: Single-dose prophylactic antibiotics are as effective as prolonged post-operative antibiotics in preventing SSIs, with the added benefits of fewer side effects, better compliance, and reduced risk of antibiotic resistance. Single-dose regimens are a safer and more efficient approach for most surgical procedures.