Abstract Objectives Electronic health record-based clinical decision support (CDS) has the potential to improve health outcomes. This systematic review investigates the design, effectiveness, and economic outcomes of CDS targeting several common chronic diseases. Material and Methods We conducted a search in PubMed (Medline), EBSCOHOST (CINAHL, APA PsychInfo, EconLit), and Web of Science. We limited the search to studies from 2011 to 2021. Studies were included if the CDS was electronic health record-based and targeted one or more of the following chronic diseases: cardiovascular disease, diabetes, chronic kidney disease, hypertension, and hypercholesterolemia. Studies with effectiveness or economic outcomes were considered for inclusion, and a meta-analysis was conducted. Results The review included 76 studies with effectiveness outcomes and 9 with economic outcomes. Of the effectiveness studies, 63% described a positive outcome that favored the CDS intervention group. However, meta-analysis demonstrated that effect sizes were heterogenous and small, with limited clinical and statistical significance. Of the economic studies, most full economic evaluations (n = 5) used a modeled analysis approach. Cost-effectiveness of CDS varied widely between studies, with an estimated incremental cost-effectiveness ratio ranging between USD$2192 to USD$151 955 per QALY. Conclusion We summarize contemporary chronic disease CDS designs and evaluation results. The effectiveness and cost-effectiveness results for CDS interventions are highly heterogeneous, likely due to differences in implementation context and evaluation methodology. Improved quality of reporting, particularly from modeled economic evaluations, would assist decision makers to better interpret and utilize results from these primary research studies. Registration PROSPERO (CRD42020203716)