BACKGROUND: Wearable technologies provide users hands-free access to computer functions and are becoming increasingly popular on both the consumer market and in various industries. The medical industry has pioneered research and implementation of head-mounted wearable devices, such as Google Glass. Most of this research has focused on surgical interventions; however, other medical fields have begun to explore the potential of this technology to support both patients and clinicians. OBJECTIVE: Our aim was to systematically evaluate the feasibility, usability, and acceptability of using Google Glass in nonsurgical medical settings and to determine the benefits, limitations, and future directions of its application. METHODS: This review covers literature published between January 2013 and May 2017. Searches included PubMed MEDLINE, Embase, INSPEC (Ebsco), Cochrane Central Register of Controlled Trials (CENTRAL), IEEE Explore, Web of Science, Scopus, and Compendex. The search strategy sought all articles on Google Glass. Two reviewers independently screened titles and abstracts, assessed full-text articles, and extracted data from articles that met all predefined criteria. Any disagreements were resolved by discussion or consultation by the senior author. Included studies were original research articles that evaluated the feasibility, usability, or acceptability of Google Glass in nonsurgical medical settings. The preferred reporting results of systematic reviews and meta-analyses (PRISMA) guidelines were followed for reporting of results. RESULTS: Of the 852 records examined, 51 met all predefined criteria, including patient-centered (n=21) and clinician-centered studies (n=30). Patient-centered studies explored the utility of Google Glass in supporting patients with motor impairments (n=8), visual impairments (n=5), developmental and psychiatric disorders (n=2), weight management concerns (n=3), allergies (n=1), or other health concerns (n=2). Clinician-centered studies explored the utility of Google Glass in student training (n=9), disaster relief (n=4), diagnostics (n=2), nursing (n=1), autopsy and postmortem examination (n=1), wound care (n=1), behavioral sciences (n=1), and various medical subspecialties, including, cardiology (n=3), radiology (n=3), neurology (n=1), anesthesiology (n=1), pulmonology (n=1), toxicology (n=1), and dermatology (n=1). Most of the studies were conducted in the United States (40/51, 78%), did not report specific age information for participants (38/51, 75%), had sample size <30 participants (29/51, 57%), and were pilot or feasibility studies (31/51, 61%). Most patient-centered studies (19/21, 90%) demonstrated feasibility with high satisfaction and acceptability among participants, despite a few technical challenges with the device. A number of clinician-centered studies (11/30, 37%) reported low to moderate satisfaction among participants, with the most promising results being in the area of student training. Studies varied in sample size, approach for implementation of Google Glass, and outcomes assessment. CONCLUSIONS: The use of Google Glass in nonsurgical medical settings varied. More promising results regarding the feasibility, usability, and acceptability of using Google Glass were seen in patient-centered studies and student training settings. Further research evaluating the efficacy and cost-effectiveness of Google Glass as an intervention to improve important clinical outcomes is warranted.