As an alternative to traditional teaching, e-learning has enabled continuity of learning for health professions students during the coronavirus disease 2019 (COVID-19) pandemic. This review explored health professions students; perceptions, acceptance, motivation, and engagement with e-learning during the COVID-19 pandemic. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review was conducted by consulting 5 databases: PubMed, ERIC (Ebsco), Science Direct, Scopus, and Web of Science. The quality of the included studies was assessed using the Medical Education Research Study Quality Instrument. The research protocol was previously registered in the PROSPERO registry (CRD42021237055). From 250 studies identified, 15 were selected with a total of 111,622 students. Mostly positive perceptions were reported in 7 of 12 studies, which mainly focused on technology access, possession of basic computer skills, pedagogical design of online courses, online interactions, and learning flexibility. However, predominantly negative perceptions were identified in 5 of 12 studies, which pointed out constraints related to internet connections, the use of educational platforms, and acquisition of clinical skills. Satisfactory levels of acceptance of distance learning were reported in 3 of 4 studies. For student motivation and engagement, 1 study reported similar or higher motivation than with traditional teaching, and another study indicated that student engagement significantly increased during the COVID-19 pandemic. Health professions students showed a positive response to e-learning regarding perceptions, acceptance, motivation, and engagement. Future research is needed to remediate the lack of studies addressing health professions students’ motivation and engagement during the COVID-19 pandemic.