Objective: The objective of this study to evaluate the efficacy of perioperative oral antibiotics in the prevention of acute infective endophthalmitis (IE) after cataract surgery. Methods: This prospective study of patients undergoing uncomplicated SICS was conducted. Group A was given post-op oral ciprofloxacin for five days, whereas Group B was not. Both groups received 5% povidone-iodine (PVI) preparation for three minutes in the conjunctival cul-de-sac preoperatively as prophylaxis. The minimum post-operative follow-up period was six weeks. Results: Out of 1856 patients, 896 (48.27%) were included in Group A, and 960 (51.72%) were included in Group B. No significant difference in anterior chamber (AC) reaction was found on day 1 (p = 0.69), day 14 (p = 0.06), or day 42 (p = 0.1). One patient developed acute post-operative infective endophthalmitis (0.04%) and one patients developed toxic anterior segment syndrome (TASS) from Group A. The non-oral antibiotic group had no serious complications. Conclusions: Perioperative oral antibiotic use in routine clinical practice is not recommended for the prevention of acute post-operative infective endophthalmitis. Pre-operative conjunctival PVI 5% for five minute was proven to be effective prophylactic measures in our study.