Background: Spaced digital education applies digital tools to deliver educational content via multiple, repeated learning sessionsseparated by prespecified time intervals. Spaced digital education appears to promote acquisition and long-term retention ofknowledge, skills, and change in clinical behavior. Objective: The aim of this review was to assess the effectiveness of spaced digital education in improving pre- and postregistrationhealth care professionals'knowledge, skills, attitudes, satisfaction, and change in clinical behavior. Methods: This review followed Cochrane's methodology and PRISMA (Preferred Reporting Items of Systematic Reviews andMeta-Analyses) reporting guidelines. We searched MEDLINE, Embase, Web of Science, ERIC, PsycINFO, CINAHL, CENTRAL,and ProQuest Dissertation and Theses databases from January 1990 to February 2023. We included randomized controlled trials(RCTs), cluster RCTs, and quasi-RCTs comparing spaced digital education with nonspaced education, spaced nondigital education,traditional learning, or no intervention for pre- or postregistration health care professionals. Study selection, data extraction, studyquality, and certainty of evidence were assessed by 2 independent reviewers. Meta-analyses were conducted using random effectmodels. Results: We included 23 studies evaluating spaced online education (n=17, 74%) or spaced digital simulation (n=6, 26%)interventions. Most studies assessed 1 or 2 outcomes, including knowledge (n=15, 65%), skills (n=9, 39%), attitudes (n=8, 35%),clinical behavior change (n=8, 35%), and satisfaction (n=7, 30%). Most studies had an unclear or a high risk of bias (n=19, 83%).Spaced online education was superior to massed online education for postintervention knowledge (n=9, 39%; standardized meandifference [SMD] 0.32, 95% CI 0.13-0.51, I2=66%, moderate certainty of evidence). Spaced online education (n=3, 13%) wassuperior to massed online education (n=2, 9%) and no intervention (n=1, 4%; SMD 0.67, 95% CI 0.43-0.91, I2=5%, moderatecertainty of evidence) for postintervention clinical behavior change. Spaced digital simulation was superior to massed simulationfor postintervention surgical skills (n=2, 9%; SMD 1.15, 95% CI 0.34-1.96, I2=74%, low certainty of evidence). Spaced digitaleducation positively impacted confidence and satisfaction with the intervention. Conclusions: Spaced digital education is effective in improving knowledge, particularly in substantially improving surgicalskills and promoting clinical behavior change in pre- and postregistration health care professionals. Our findings support the use f spaced digital education interventions in undergraduate and postgraduate health profession education. Trial Registration:PROSPERO CRD42021241969; Trial Registration: PROSPERO CRD42021241969; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=241969