Background The clinical decision support systems(CDSSs) for prescription medications is one of the technologies aimed at improving physician practice behavior and patient outcomes by reducing drug prescription errors. This study was conducted to investigate the effect of various CDSSs on physician practice behavior and patient outcomes.Methods This systematic review was conducted by searching in PubMed, EMBASE, Web of Science, Scopus and Cochrane Library from January 2005 to November 2019. Two researchers independently evaluated the studies. Any discrepancies over the eligibility of the studies between the two researchers were then resolved by consulting a third researcher. Finally, data were extracted from the articles; however, we could not able to conduct meta-analysis due to the heterogeneity of the studies and the narrative form of the findings.Results Based on the inclusion criteria, 46 studies were considered eligible for the analysis in this review. The CDSS for prescription medications had been used for various diseases, namely cardiovascular diseases, hypertension, diabetes, gastrointestinal and respiratory diseases, AIDS, appendicitis, kidney disease, malaria, high blood potassium, mental disease. Meanwhile, other cases such as the concurrent prescription of multiple drugs for the patient and its effects on the above-mentioned outcomes were evaluated. The analysis shows that in some cases the application of CDSS provides positive effects on patient outcomes and physician practice behaviors. No significant difference was observed in comparison between some other cases and conventional methods. We think that this could be due to the disease type, the quantity and type of CDSS requirements that influence the comparison.Conclusions Our findings suggest that the positive effects of the CDSS are due to factors such as user-friendliness, compliance with clinical guidelines, patient and doctor cooperation, integration of electronic health records, CDSS and pharmaceutical systems, consideration of the views of physicians in assessing the importance of CDSS alerts and their real-time alerts in the prescription.Registration number on PROSPERO CRD42018079936.