OBJECTIVE: To systematically synthesize and appraise the evidence on the effectiveness of health information technology (HIT)-based discharge care transition interventions (CTIs) on readmissions and emergency room visits. MATERIALS AND METHODS: We conducted a systematic search on multiple databases (MEDLINE, CINAHL, EMBASE, and CENTRAL) on June 29, 2020, targeting readmissions and emergency room visits. Prospective studies evaluating HIT-based CTIs published as original research articles in English language peer-reviewed journals were eligible for inclusion. Outcomes were pooled for narrative analysis. RESULTS: Eleven studies were included for review. Most studies (n = 6) were non-RCTs. Several studies (n = 9) assessed bridging interventions comprised of at least 1 pre- and 1 post-discharge component. The narrative analysis found improvements in patient experience and perceptions of discharge care. DISCUSSION: Given the statistical and clinical heterogeneity among studies, we could not ascertain the cumulative effect of CTIs on clinical outcomes. Nevertheless, we found gaps in current research and its implications for future work, including the need for a HIT-based care transition model for guiding theory-driven design and evaluation of HIT-based discharge CTIs. CONCLUSIONS: We appraised and aggregated empirical evidence on the cumulative effectiveness of HIT-based interventions to support discharge transitions from hospital to home, and we highlighted the implications for evidence-based practice and informatics research.