Background: Inappropriate antibiotic prescription is one of the key contributors to antibiotic resistance, which is managed with a range of interventions including education. Objective: We aimed to summarize evidence on the effectiveness of digital education of antibiotic management compared to traditional education for improving health care professionals’ knowledge, skills, attitudes, and clinical practice. Methods: Seven electronic databases and two trial registries were searched for randomized controlled trials (RCTs) and cluster RCTs published between January 1, 1990, and September 20, 2018. There were no language restrictions. We also searched the International Clinical Trials Registry Platform Search Portal and metaRegister of Controlled Trials to identify unpublished trials and checked the reference lists of included studies and relevant systematic reviews for study eligibility. We followed Cochrane methods to select studies, extract data, and appraise and synthesize eligible studies. We used random-effect models for the pooled analysis and assessed statistical heterogeneity by visual inspection of a forest plot and calculation of the I2 statistic. Results: Six cluster RCTs and two RCTs with 655 primary care practices, 1392 primary care physicians, and 485,632 patients were included. The interventions included personal digital assistants; short text messages; online digital education including emails and websites; and online blended education, which used a combination of online digital education and traditional education materials. The control groups received traditional education. Six studies assessed postintervention change in clinical practice. The majority of the studies (4/6) reported greater reduction in antibiotic prescription or dispensing rate with digital education than with traditional education. Two studies showed significant differences in postintervention knowledge scores in favor of mobile education over traditional education (standardized mean difference=1.09, 95% CI 0.90-1.28; I2=0%; large effect size; 491 participants [2 studies]). The findings for health care professionals’ attitudes and patient-related outcomes were mixed or inconclusive. Three studies found digital education to be more cost-effective than traditional education. None of the included studies reported on skills, satisfaction, or potential adverse effects. Conclusions: Findings from studies deploying mobile or online modalities of digital education on antibiotic management were complementary and found to be more cost-effective than traditional education in improving clinical practice and postintervention knowledge, particularly in postregistration settings. There is a lack of evidence on the effectiveness of other digital education modalities such as virtual reality or serious games. Future studies should also include health care professionals working in settings other than primary care and low- and middle-income countries.