BACKGROUND: Children have busy daily schedules, making school an ideal setting for promoting health-enhancing exercise behavior. However, children with mobility disabilities have limited exercise options to improve their cardiorespiratory fitness and cardiometabolic health. OBJECTIVE: This study aims to test the feasibility of implementing a virtual reality (VR) exercise program for children with mobility disabilities in a high school setting. METHODS: A pre- to posttrial single-group design with a 6-week exercise intervention was conducted at a high school. The study aimed to enroll up to 12 students with a disability. Participants were given the option of exercising at home or school. The exercise prescription was three 25-minute sessions per week at a moderate intensity, using a head-mounted VR display. School exercise sessions were supervised by research staff. Home exercise sessions were performed autonomously. Several implementation metrics of feasibility were recorded, including exercise attendance, volume, adverse events or problems, and benefits related to health-related fitness (walking endurance and hand-grip strength). The study also included a qualitative evaluation of critical implementation factors and potential benefits for participants that were not included in the study measures. Outcomes were descriptively analyzed, and 2-tailed t tests were used as appropriate. RESULTS: In total, 10 students enrolled in the program and 9 completed the study (mean age 17, SD 0.6 y). In total, 5 (56%) participants exercised at school, and 4 (44%) exercised at home; 1 participant dropped out prior to exercise. The mean attendance for all 9 completers was 61.1% (11/18 sessions). The mean exercise minutes per week was 35.5 (SD 22) minutes. The mean move minutes per session was 17.7 (SD 11) minutes. The mean minutes per session was 18 (SD 1.4) minutes for school exercisers and 17 (SD 18) minutes for home exercisers, indicating variable responses from home exercisers. The mean rating of perceived exertion per exercise session was 4.3 (SD 2), indicating a moderate intensity that ranged from low to hard intensity. No adverse events or problems were identified. No improvements in walking endurance or hand-grip strength were observed. School exercisers achieved a higher attendance rate (83%) than home exercisers (27%; P<.001) and seemingly had a 2-fold increase in the volume of exercise achieved (school: mean 279, SD 55 min; 95% CI 212-347; home: mean 131, SD 170 min; 95% CI -140 to 401; P=.10). Qualitative themes relating to implementation factors and benefits to participant well-being were identified. CONCLUSIONS: This study identified factors to inform an optimal protocol for implementing a high school-based VR exercise program for children with disabilities. Study findings demonstrated that moderate exercise at school is feasible in VR, but simply providing children with VR exergaming technology at home, without coaching, will not successfully engage them in exercise.