Background <p>Access to mental health care remains a considerable challenge in the United States, with long wait times, provider shortages, and structural barriers limiting treatment for half of American adults. Prescription digital therapeutics (PDTs) – evidence-based health software designed to diagnose, treat, and/or mitigate specific diseases – represent an opportunity to address this problem, yet their use remains limited. While previous studies have broadly identified barriers to and facilitators of the adoption of digital health interventions, no systematic literature review to date has synthesized interest holder perceptions across patients, providers, and healthcare administrators. This systematic literature review aimed to understand interest holder perceptions of prescription digital therapeutics (PDTs) in mental health care, identifying barriers to and facilitators of their use. A comprehensive search was conducted in June 2025 via Google Scholar and PubMed, supplemented by forward and backward searches of the obtained publications. Eligible studies were open-access, peer-reviewed articles published since January 2020 that presented original research on the adoption of PDTs by patients, providers, or healthcare administrators. Study quality and risk of bias were assessed via a modified risk of bias in systematic reviews (ROBIS) tool. The findings were synthesized thematically by interest holder groups and categorized into barriers to and facilitators of PDT engagement.</p> Results <p>The search yielded 116 abstracts for screening. Eleven studies, representing 4,484 total participants (2,945 patients, 1,525 providers, and 14 healthcare administrators), met the inclusion criteria. The identified barriers included low awareness, low digital literacy, poor usability, and concerns related to workflow disruptions; the facilitators included clinical evidence, provider confidence, and ease of use. Shared and unique barriers and facilitators across interest holders were identified and framed within the UTAUT framework.</p> Conclusion <p>Interest holder perceptions highlight both promising indicators of adoption and persistent challenges in implementing PDTs in mental health care, underscoring the need for targeted provider education, clearer reimbursement pathways, and improved patient awareness. Future studies using more diverse methods and outcome measures could further strengthen the understanding of factors influencing PDT adoption across interest holders.</p>