Background Leptospirosis is a worldwide prevalent zoonosis and chronic kidney disease (CKD) is a leading global disease burden. Because of pathophysiological changes in the kidney, it has been suggested that these conditions may be associated. However, the extent of this interaction has not been synthetized. We aimed to systematically review and critically appraise the evidence on the association between leptospirosis and CKD. Methodology/Principal findings Observational studies with a control group were selected. Leptospirosis, confirmed with laboratory methods, and CKD also based on a laboratory assessment, were the exposures and outcomes of interest. The search was conducted in EMBASE, MEDLINE, Global Health, Scopus and Web of Science. Studies selected for qualitative synthesis were assessed for risk of bias following the Newcastle-Ottawa Scale. 5,981 reports were screened, and 2 (n = 3,534) were included for qualitative synthesis. The studies were conducted in Taiwan and Nicaragua; these reported cross-sectional and longitudinal estimates. In the general population, the mean estimated glomerular filtration rate (eGFR) was lower (p<0.001) in people testing positive for antileptospira antibodies (eGFR = 98.3) than in negative controls (eGFR = 100.8). Among sugarcane applicants with high creatinine, those who were seropositive had lower eGFR (mean difference:-10.08). In a prospective analysis, people with high antileptospira antibodies titer at baseline and follow-up, had worse eGFR (p<0.05). Conclusion Although the available evidence suggests there may be a positive association between leptospirosis and CKD, whereby leptospirosis could be a risk factor for CKD, it is still premature to draw conclusions. There is an urgent need for research on this association.