In the world reference context, although virtual reality, augmented reality and mixed reality have been emerging methodologies for several years, only today technological and scientific advances have made them suitable to revolutionize clinical care and medical contexts through the provision of enhanced functionalities and improved health services. This systematic review provides the state-of-the-art applications of the Microsoft HoloLens 2 in a medical and healthcare context. Focusing on the potential that this technology has in providing digitally supported clinical care, also but not only in relation to the COVID-19 pandemic, studies that proved the applicability and feasibility of HoloLens 2 in a medical and healthcare scenario were considered. The review presents a thorough examination of the different studies conducted since 2019, focusing on HoloLens 2 medical sub-field applications, device functionalities provided to users, software/platform/framework used, as well as the study validation. The results provided in this paper could highlight the potential and limitations of the HoloLens 2-based innovative solutions and bring focus to emerging research topics, such as telemedicine, remote control and motor rehabilitation.