BACKGROUND: The coronavirus disease (COVID-19) pandemic has led to rapid acceleration in the deployment of new digital technologies to improve both accessibility to and quality of care, and to protect staff. Mixed-reality (MR) technology is the latest iteration of telemedicine innovation; it is a logical next step in the move toward the provision of digitally supported clinical care and medical education. This technology has the potential to revolutionize care both during and after the COVID-19 pandemic. OBJECTIVE: This pilot project sought to deploy the HoloLens2 MR device to support the delivery of remote care in COVID-19 hospital environments. METHODS: A prospective, observational, nested cohort evaluation of the HoloLens2 was undertaken across three distinct clinical clusters in a teaching hospital in the United Kingdom. Data pertaining to staff exposure to high-risk COVID-19 environments and personal protective equipment (PPE) use by clinical staff (N=28) were collected, and assessments of acceptability and feasibility were conducted. RESULTS: The deployment of the HoloLens2 led to a 51.5% reduction in time exposed to harm for staff looking after COVID-19 patients (3.32 vs 1.63 hours/day/staff member; P=.002), and an 83.1% reduction in the amount of PPE used (178 vs 30 items/round/day; P=.02). This represents 222.98 hours of reduced staff exposure to COVID-19, and 3100 fewer PPE items used each week across the three clusters evaluated. The majority of staff using the device agreed it was easy to set up and comfortable to wear, improved the quality of care and decision making, and led to better teamwork and communication. In total, 89.3% (25/28) of users felt that their clinical team was safer when using the HoloLens2. CONCLUSIONS: New technologies have a role in minimizing exposure to nosocomial infection, optimizing the use of PPE, and enhancing aspects of care. Deploying such technologies at pace requires context-specific information security, infection control, user experience, and workflow integration to be addressed at the outset and led by clinical end-users. The deployment of new telemedicine technology must be supported with objective evidence for its safety and effectiveness to ensure maximum impact.