BACKGROUND: The shortage and disproportionate distribution of health care workers worldwide is further aggravated by the inadequacy of training programs, difficulties in implementing conventional curricula, deficiencies in learning infrastructure, or a lack of essential equipment. Offline digital education has the potential to improve the quality of health professions education. OBJECTIVE: The primary objective of this systematic review was to evaluate the effectiveness of offline digital education compared with various controls in improving learners' knowledge, skills, attitudes, satisfaction, and patient-related outcomes. The secondary objectives were (1) to assess the cost-effectiveness of the interventions and (2) to assess adverse effects of the interventions on patients and learners. METHODS: We searched 7 electronic databases and 2 trial registries for randomized controlled trials published between January 1990 and August 2017. We used Cochrane systematic review methods. RESULTS: A total of 27 trials involving 4618 individuals were included in this systematic review. Meta-analyses found that compared with no intervention, offline digital education (CD-ROM) may increase knowledge in nurses (standardized mean difference [SMD]=1.88; 95% CI 1.14 to 2.62; participants=300; studies=3; I=80%; low certainty evidence). A meta-analysis of 2 studies found that compared with no intervention, the effects of offline digital education (computer-assisted training [CAT]) on nurses and physical therapists' knowledge were uncertain (SMD 0.55; 95% CI -0.39 to 1.50; participants=64; I=71%; very low certainty evidence). A meta-analysis of 2 studies found that compared with traditional learning, a PowerPoint presentation may improve the knowledge of patient care personnel and pharmacists (SMD 0.76; 95% CI 0.29 to 1.23; participants=167; I=54%; low certainty evidence). A meta-analysis of 4 studies found that compared with traditional training, the effects of computer-assisted training on skills in community (mental health) therapists, nurses, and pharmacists were uncertain (SMD 0.45; 95% CI -0.35 to 1.25; participants=229; I=88%; very low certainty evidence). A meta-analysis of 4 studies found that compared with traditional training, offline digital education may have little effect or no difference on satisfaction scores in nurses and mental health therapists (SMD -0.07; 95% CI -0.42 to 0.28, participants=232; I=41%; low certainty evidence). A total of 2 studies found that offline digital education may have little or no effect on patient-centered outcomes when compared with blended learning. For skills and attitudes, the results were mixed and inconclusive. None of the studies reported adverse or unintended effects of the interventions. Only 1 study reported costs of interventions. The risk of bias was predominantly unclear and the certainty of the evidence ranged from low to very low. CONCLUSIONS: There is some evidence to support the effectiveness of offline digital education in improving learners' knowledge and insufficient quality and quantity evidence for the other outcomes. Future high-quality studies are needed to increase generalizability and inform use of this modality of education.