Polymyxins are last-resort antibiotics re-emerged to treat infections caused by multidrug resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacterial infections. However, polymyxin-associated nephrotoxicity has become the main safety concern. Therefore, we conducted this systematic review and meta-analysis on polymyxin-induced nephrotoxicity and its predictors using studies conducted based on the validated RIFLE (Risk, Injury, Failure, Loss of Function and End-stage renal disease) criteria of acute kidney damage. Literature search was carried out through visiting legitimate databases and indexing services including PubMed, MEDLINE (Ovid®), EMBASE (Ovid®), and Scopus to retrieve relevant studies. Following screening and eligibility evaluation, relevant data were extracted from included studies and analyzed using STATA 15.0 and Rev-Man 5.3. Inverse variance method with random effects pooling model was used for the analysis of outcome measures at 95% confidence interval. Besides, meta-regression, meta-influence, and publication bias analyses were conducted. A total of 48 studies involving 6,199 adult patients aged ≥ 18 years were included for systematic review and meta-analysis. The pooled incidence of polymyxin-induced nephrotoxicity was found to be 45% (95% CI: 41- 49%; I² = 92.52%). Stratifying with RIFLE severity scales, pooled estimates of polymyxin-treated patients identified as 'risk', 'injury' and 'failure' were 17% (95% CI: 14-20%), 13% (95% CI: 11-15%), and 10% (95% CI: 9-11%), respectively. Besides, the pooled incidence of colistin-induced nephrotoxicity was about 48% (95% CI: 42-54%), whereas that of polymyxin B was 38% (95% CI: 32-44%). Likewise, colistin had 37% increased risk of developing nephrotoxicity compared to the polymyxin B treated cohorts (RR = 1.37, 95% CI: 1.13-1.67; I² = 57%). Older age (AOR = 1.03, 95% CI: 1.01-1.05), daily dose (AOR = 1.46, 95% CI: 1.09-1.96), underlying diabetes mellitus (AOR = 1.81, 95% CI: 1.25-2.63), and concomitant nephrotoxic drugs (AOR = 2.31, 95% CI: 1.79-3.00) were independent risk factors for polymyxin-induced nephrotoxicity. Patients with high serum albumin level were less likely (AOR = 0.69, 95% CI: 0.56-0.85] to experience nephrotoxicity compared to those with low albumin level. Despite the resurgence of these antibiotics for the chemotherapy of MDR/XDR-Gram-negative superbugs, the high incidence of nephrotoxicity has become a contemporary clinical concern. Being elderly, high daily dose, having underlying diseases such as diabetes, and use of concomitant nephrotoxic drugs were independent predictors of nephrotoxicity. Therefore, therapeutic drug monitoring should be done to these patients to outweigh the potential benefits of polymyxin therapy from its risk.