Background Based on endophthalmitis vitrectomy study, intravitreal injection of antibiotics is preferred for initial management of cases of acute post cataract surgery endophthalmitis (APCE) with presenting vision of hand motions (HM). This study aimed to compare outcomes of early and complete vitrectomy (VIT) and vitreous tap and antibiotic injection (T&I) in cases of APCE presented with vision of HM. Methods In this prospective study, cases of APCE with vision of HM between 2018 and 2020 were enrolled. According to the time of presentation, the patients were arranged into two groups (VIT vs. T&I). Demographic data, elapsed time to developing endophthalmitis, past medical history, microbiology results, complications, and final visual acuity were recorded and analyzed. Results Seventy-six eyes of 76 patients were enrolled. Fifty-three eyes underwent T&I and twenty-three were arranged into the VIT group. Past medical history of 34.2% of patients was significant for diabetes mellitus. There was a statistically significant lower logMAR in VIT group compared to T&I group (diff = 0.14, 95% CI: 0.04 to 0.24, P-value = 0.007). The comparison of the diabetic and non-diabetic patients in both groups showed that the visual outcome was better in non-diabetic cases compared to the diabetic subjects. There was no statistically significant difference between the diabetic and non-diabetic groups regarding the superiority of procedure. Conclusion Based on our results, we could recommend that it’s maybe better to do early and complete vitrectomy as the initial management of APCE with the vision of HM. Past medical history of diabetes mellitus is not a determining factor for choosing initial management between vitrectomy and antibiotic injection.