Background The COVID-19 pandemic has increased the impact and spread of mental illness and made health services difficult to access; therefore, there is a need for remote, pervasive forms of mental health monitoring. Digital phenotyping is a new approach that uses measures extracted from spontaneous interactions with smartphones (eg, screen touches or movements) or other digital devices as markers of mental status. Objective This review aimed to evaluate the feasibility of using digital phenotyping for predicting relapse or exacerbation of symptoms in patients with mental disorders through a systematic review of the scientific literature. Methods Our research was carried out using 2 bibliographic databases (PubMed and Scopus) by searching articles published up to January 2023. By following the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines, we started from an initial pool of 1150 scientific papers and screened and extracted a final sample of 29 papers, including studies concerning clinical populations in the field of mental health, which were aimed at predicting relapse or exacerbation of symptoms. The systematic review has been registered on the web registry Open Science Framework. Results We divided the results into 4 groups according to mental disorder: schizophrenia (9/29, 31%), mood disorders (15/29, 52%), anxiety disorders (4/29, 14%), and substance use disorder (1/29, 3%). The results for the first 3 groups showed that several features (ie, mobility, location, phone use, call log, heart rate, sleep, head movements, facial and vocal characteristics, sociability, social rhythms, conversations, number of steps, screen on or screen off status, SMS text message logs, peripheral skin temperature, electrodermal activity, light exposure, and physical activity), extracted from data collected via the smartphone and wearable wristbands, can be used to create digital phenotypes that could support gold-standard assessment and could be used to predict relapse or symptom exacerbations. Conclusions Thus, as the data were consistent for almost all the mental disorders considered (mood disorders, anxiety disorders, and schizophrenia), the feasibility of this approach was confirmed. In the future, a new model of health care management using digital devices should be integrated with the digital phenotyping approach and tailored mobile interventions (managing crises during relapse or exacerbation).