Background Antioxidants show nephroprotective effect against vancomycin associated nephrotoxicity (VAN) in animals. This study aimed to assess the ascorbic acid nephro-protective role against VAN clinically. Methods Forty-one critically ill patients were randomly assigned to one of two groups: intervention group (vancomycin IV plus ascorbic acid, n=21) or control group (vancomycin IV only, n=20). Primary outcomes were the incidence of VAN and the absolute change in creatinine parameters, while mortality rate was the secondary outcome. Nephrotoxicity was defined as an increase in serum creatinine (S.cr) by at least 0.5 mg/dL or 50% of baseline for at least two successive measurements. This study is registered at Clinicaltrials.gov (NCT03921099), April 2019. Results Mean absolute S.cr increase was significant when compared between both groups, P-value = 0.036, where S.cr increased by 0.05(0.12) and 0.34(0.55) mg/dL in the intervention and control groups, respectively. Mean absolute Cr.cl decline was significant when compared between both groups, P-value = 0.04, where Cr.cl was decreased by 5.9(17.8) and 22.3(30.4) ml/min in the intervention and control groups, respectively. Incidence of VAN was 1/21(4.7%) versus 5/20(25%) in the intervention and control groups, respectively (RR: 0.19; CI: 0.024–1.49; P-value = 0.093). Mortality was higher in the control group; however, it was not statistically significant, P-value = 0.141. Conclusion Co-administration of ascorbic acid with vancomycin preserved renal function and reduced the absolute risk of VAN by 20.3%, however, the reduction in VAN incidence didn’t reach statistical significance level. Further large multicenter prospective trials are recommended.