We performed a systematic review and meta-analysis to determine whether the use of local antibiotics is a beneficial prophylactic treatment for endophthalmitis in patients treated with anti-VEGF agents. We searched the MEDLINE and EMBASE databases, and the Cochrane Library over the period January 2007 to December 2016. The search terms used included “Endophthalmitis”, “Antibiotic” and “Intravitreal injection”. Studies in which the patients were treated exclusively with intravitreal injections of anti-VEGF were selected. Eight studies fit the inclusion criteria, which included a total of 276,774 injections; 109,178 (39.45%) were associated with the use of antibiotics and 114,821 (60.55%) were not associated with the use of antibiotics. Our meta-analysis indicated a significant risk for endophthalmitis that was 1.70 times greater with the use of antibiotics than that without antibiotics, with a confidence interval of 1.08 to 2.66 (p = 0.02). A meta-regression indicated that the location (operating rooms versus outpatient clinics) of injection did not have a significant effect on the incidence of endophthalmitis. The prophylactic use of antibiotics when administering anti-VEGF intravitreal injections may contribute to a greater incidence of endophthalmitis. This finding, in addition to reducing costs, would eliminate a treatment that has been shown to be unnecessary and even harmful to patients.