ObjectiveConsiderable international investment in hospital electronic prescribing (ePrescribing) systems has been made, but despite this, it is proving difficult for most organizations to realize safety, quality, and efficiency gains in prescribing. The objective of this work was to develop policy-relevant insights into the optimization of hospital ePrescribing systems to maximize the benefits and minimize the risks of these expensive digital health infrastructures.MethodsWe undertook a systematic scoping review of the literature by searching MEDLINE, Embase, and CINAHL databases. We searched for primary studies reporting on ePrescribing optimization strategies and independently screened and abstracted data until saturation was achieved. Findings were theoretically and thematically synthesized taking a medicine life-cycle perspective, incorporating consultative phases with domain experts.ResultsWe identified 23,609 potentially eligible studies from which 1367 satisfied our inclusion criteria. Thematic synthesis was conducted on a data set of 76 studies, of which 48 were based in the United States. Key approaches to optimization included the following: stakeholder engagement, system or process redesign, technological innovations, and education and training packages. Single-component interventions (n = 26) described technological optimization strategies focusing on a single, specific step in the prescribing process. Multicomponent interventions (n = 50) used a combination of optimization strategies, typically targeting multiple steps in the medicines management process.DiscussionWe identified numerous optimization strategies for enhancing the performance of ePrescribing systems. Key considerations for ePrescribing optimization include meaningful stakeholder engagement to reconceptualize the service delivery model and implementing technological innovations with supporting training packages to simultaneously impact on different facets of the medicines management process.