Abstract Background Propensity score methods are becoming increasingly popular in infectious disease medicine to correct for confounding in observational studies. However, applying and reporting propensity score techniques correctly requires substantial knowledge of these methods. The quality of conduct and reporting of propensity score methods in studies investigating the effectiveness of antimicrobial therapy is yet undetermined. Methods A systematic review was performed to provide an overview of studies (2005–2020) on the effectiveness of antimicrobial therapy that used propensity score methods. A quality assessment tool and a standardized quality score were developed to evaluate a subset of studies in which antibacterial therapy was investigated in detail. The scale of this standardized score ranges between 0 (lowest quality) and 100 (excellent). Results A total of 437 studies were included. The absolute number of studies that investigated the effectiveness of antimicrobial therapy and that used propensity score methods increased 15-fold between the periods 2005–2009 and 2015–2019. Propensity score matching was the most frequently applied technique (65%), followed by propensity score–adjusted multivariable regression (25%). A subset of 108 studies was evaluated in detail. The median standardized quality score per year ranged between 53 and 61 (overall range: 33–88) and remained constant over the years. Conclusions The quality of conduct and reporting of propensity score methods in research on the effectiveness of antimicrobial therapy needs substantial improvement. The quality assessment instrument that was developed in this study may serve to help investigators improve the conduct and reporting of propensity score methods.