BACKGROUND: Decentralized health systems in low- and middle-income countries (LMICs) affected by humanitarian crises lack resources and a qualified workforce to attend to the overwhelming demand for mental health care in emergencies. Innovative approaches that are safe, cost-effective, and scalable are needed to address the burden of traumatic stress caused by emergencies. High mobile phone ownership rates combined with the precision of neural, cognitive, and biometric measures of trauma and their feasible integration with artificial intelligence makes digital app interventions a promising pathway to promote precision diagnosis and high-impact care. OBJECTIVE: This study aimed to advance methods for the objective diagnosis and treatment of trauma in emergencies across LMICs by examining neural, cognitive, and biometric markers and the efficacy of the eResilience app, a neuroscience-informed mobile health mental health app intervention, via changes in clinical symptomatology, cognitive performance, and brain activity. METHODS: Trauma-exposed African refugees residing in Australia were selected for this study. A research software version of the eResilience app with advanced monitoring capabilities was designed for this trial. Participants completed the eResilience app at home during a 7-day period. Clinical, cognitive, and electrophysiological data were collected at baseline, along with posttest measurements to examine biomarkers of trauma and the efficacy of the proposed digital intervention for the treatment of trauma and its potential outcomes, including depression, anxiety, physical symptoms, self-harm, substance misuse, and cognitive impairment. In addition, biofeedback, well-being, and subjective stress data points were collected via the app during the treatment week, followed by clinical interviews at 1, 3, 6, and 12 months after the intervention. RESULTS: Data collection was conducted between 2018 and 2020. A total of 100 participants exposed to war were screened; 75 (75%) were enrolled and assigned to a trauma-exposed control (38/75, 51%) or posttraumatic stress disorder condition (37/75, 49%); and 70 (70%) completed all baseline, treatment, and posttest assessments. A total of 89% (62/70) of those who completed the intervention opted to enroll in the 3-, 6-, and 12-month follow-ups. Data collection is complete. As of May 2022, the results of all proposed analyses are being prepared for publication. If proven efficacious, this proof-of-concept clinical trial will inform fully powered randomized clinical trials in LMICs to further develop artificial intelligence-powered, app-based diagnostic and prognostic features and determine the app's cross-cultural efficacy for the treatment of trauma in emergency settings. CONCLUSIONS: This protocol provides researchers with a comprehensive background of the study rationale, a detailed guideline for replication studies interested in examining the feasibility and efficacy of the eResilience app across varied demographics, and a robust framework for investigating low-cost objective diagnostic markers in mental health interventions. Methodological limitations and suggestions are also provided. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001205426; https://tinyurl.com/yckwc4d7. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/38223.