Medication-related problems (MRPs) are an important healthcare problem. This study aimed at reviewing the published literature in Ethiopia to estimate the prevalence of MRPs and to summarize associated factors. A comprehensive systematic search was conducted in PubMed, EMBASE, CINAHL, Scopus, Google Scholar, and Google databases from inception to April 2020. Articles that addressed MRPs were eligible for inclusion. Article screening, data extraction, and study quality analysis were performed independently by two reviewers. Studies targeting specific disease condition were considered as specific, while the remaining were nonspecific. The prevalence of MRPs was then computed in medians and interquartile ranges (IQR), while associated factors were summarized in a table. Of the thirty-two studies included in this review, the majority of them (n = 24) targeted MRPs, while the remaining studies (n = 8) investigated adverse drug reactions (ADRs). Studies varied in the study design, study population, and definition of MRPs and ADRs used. The overall median prevalence was 70.8% (IQR = 61.0-80.2) with a range of 16.0% to 88.7%. The median prevalence of MRPs in specific and nonspecific patients was 71.2% (IQR = 60.7-71.2) and 69.3% (IQR = 60.7-82.0), respectively. In addition, a median of 36.6% (IQR = 10.0-85.7) of patients experienced ADRs. Indication-related and effectiveness-related MRPs were commonly reported in both specific and nonspecific patients, while noncompliance MRPs were more prevalent among specific patients than nonspecific patients. Increasing age, presence of co-morbidity, and an increasing number of drugs were the commonly identified contributing factors of MRPs. The review showed that more than two-thirds of the study participants developed MRPs. Hence, an integrated approach should be designed to improve the optimal use of pharmacotherapy to reduce the burden of MRPs. Further, future research should be undertaken to prepare cost-effective and efficient prevention mechanisms to reduce or halt the development of MRPs.