BACKGROUND: Adolescents with disabilities experience alarmingly higher rates of depression and isolation than peers without disabilities. There is a need to identify interventions that can improve mental health and isolation among this underserved population. Innovations in virtual reality (VR) gaming "standalone" headsets allow greater access to immersive high-quality digital experiences, due to their relatively low cost. OBJECTIVE: This study had three purposes, which were to (1) examine the preliminary effects of a low-cost, home-based VR multiplayer recreation and socialization on depression, socialization, and loneliness; (2) quantify the acceptability of the program as measured by participant adherence, total play time, and exercise time; and (3) identify and describe behavioral mechanisms that affected participant engagement. METHODS: This was a single-group, pre- to postdesign trial. The intervention was conducted at home. Participants were recruited from a children's hospital. The intervention lasted 4 weeks and included 2×1-hour sessions per week of supervised peer-to-peer gaming. Participants used the Meta Quest 2 headset to meet peers and 2 coaches in a private party held digitally. Aim 1 was evaluated with the Children's Depression Inventory 2 Short Form and the University of California, Los Angeles Loneliness Scale 20 items, which are measures of social isolation and loneliness, respectively. Aim 2 was evaluated through the following metrics: participant adherence, the types of games played, friendship building and playtime, and program satisfaction and enjoyment. RESULTS: In total, 12 people enrolled (mean age 16.6, SD 1.8 years; male: n=9 and female: n=3), and 8 people completed the program. Mean attendance for the 8 participants was 77% (49 sessions of 64 total possible sessions; mean 6, SD 2 sessions). A trend was observed for improved Children's Depression Inventory 2 Short Form scores (mean preintervention score 7.25, SD 4.2; mean postintervention score 5.38, SD 4.1; P=.06; effect size=0.45, 95% CI -0.15 to 3.9), but this was not statistically significant; no difference was observed for University of California, Los Angeles Loneliness Scale 20 items scores. Most participants (7/8, 88%) stated that they became friends with a peer in class; 50% (4/8) reported that they played with other people. Participants reported high levels of enjoyment and satisfaction with how the program was implemented. Qualitative analysis resulted in 4 qualitative themes that explained behavioral mechanisms that determined engagement in the program. CONCLUSIONS: The study findings demonstrated that a brief VR group program could be valuable for potentially improving mental health among adolescents with physical disabilities. Participants built friendships with peers and other players on the web, using low-cost consumer equipment that provided easy access and strong scale-up potential. Study findings identified factors that can be addressed to enhance the program within a larger clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05259462; https://clinicaltrials.gov/study/NCT05259462. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/42651.