Background: Trail running is characterised by large elevation gains/losses and uneven varying running surfaces. Limited information is available on injury and illness among trail runners to help guide injury and illness prevention strategies. Objective: The primary aim of this review was to describe the epidemiology of injury and illness among trail runners. Methods: Eight electronic databases were systematically searched (MEDLINE Ovid, PubMed, Scopus, SportsDiscus, CINAHL, Health Source: Nursing/Academic, Health Source: Consumer Ed., and Cochrane) from inception to November 2020. The search was conducted according to the PRISMA statement and the study was registered on PROSPERO international prospective register of systematic reviews (CRD42019135933). Full-text English and French studies that investigated injury and/or illness among trail runners participating in training/racing were included. The main outcome measurements included: trail running injury (incidence, prevalence, anatomical site, tissue type, pathology-type/specific diagnosis, severity), and illness (incidence, prevalence, symptoms, specific diagnosis, organ system, severity). The methodological quality of the included studies was assessed using an adapted Downs and Black assessment tool. Results: Sixteen studies with 8644 participants were included. Thirteen studies investigated race-related injury and/or illness and three studies included training-related injuries. The overall incidence range was 1.6–4285.0 injuries per 1000 h of running and 65.0–6676.6 illnesses per 1000 h of running. The foot was the most common anatomical site of trail running injury followed by the knee, lower leg, thigh, and ankle. Skin lacerations/abrasions were the most common injury diagnoses followed by skin blisters, muscle strains, muscle cramping, and ligament sprains. The most common trail running illnesses reported related to the gastro-intestinal tract (GIT), followed by the metabolic, and cardiovascular systems. Symptoms of nausea and vomiting related to GIT distress and dehydration were commonly reported. Conclusion: Current trail running literature consists mainly of injury and illness outcomes specifically in relation to single-day race participation events. Limited evidence is available on training-related injury and illness in trail running. Our review showed that injury and illness are common among trail runners, but certain studies included in this review only focused on dermatological injuries (e.g. large number of feet blisters) and GIT symptoms. Specific areas for future research were identified that could improve the management of trail running injury and illness.