Background Health care systems have become increasingly more reliant on patients’ ability to navigate the digital world. However, little research has been conducted on why some communities are less able or less likely to successfully engage with digital health technologies (DHTs), particularly among culturally and linguistically diverse (CaLD) populations. Objective This systematic review aimed to determine the barriers to and facilitators of interacting with DHTs from the perspectives of CaLD population groups, including racial or ethnic minority groups, immigrants and refugees, and Indigenous or First Nations people. Methods A systematic review and thematic synthesis of qualitative studies was conducted. Peer-reviewed literature published between January 2011 and June 2022 was searched across 3 electronic databases. Terms for digital health were combined with terms for cultural or linguistic diversity, ethnic minority groups, or Indigenous and First Nations people and terms related to barriers to accessing digital technologies. A qualitative thematic synthesis was conducted to identify descriptive and analytical themes of barriers to and facilitators of interacting with DHTs. Quality appraisal was performed using the Mixed Methods Appraisal Tool. Results Of the 1418 studies identified in the electronic search, a total of 34 (2.4%) were included in this review. Half of the included studies (17/34, 50%) were conducted in the United States. There was considerable variation in terms of the CaLD backgrounds of the participants. In total, 26% (9/34) of the studies focused on Indigenous or First Nations communities, 41% (14/34) were conducted among ethnic minority populations, 15% (5/34) of the studies were conducted among immigrants, and 18% (6/34) were conducted in refugee communities. Of the 34 studies, 21 (62%) described the development or evaluation of a digital health intervention, whereas 13 (38%) studies did not include an intervention but instead focused on elucidating participants’ views and behaviors in relation to digital health. From the 34 studies analyzed, 18 descriptive themes were identified, each describing barriers to and facilitators of interacting with DHTs, which were grouped into 7 overarching analytical themes: using technology, design components, language, culture, health and medical, trustworthiness, and interaction with others. Conclusions This study identified several analytic and descriptive themes influencing access to and uptake of DHTs among CaLD populations, including Indigenous and First Nations groups. We found that cultural factors affected all identified themes to some degree and that cultural and linguistic perspectives should be considered in the design and delivery of DHTs, with this best served through the inclusion of the target communities at all stages of development. This may improve the potential of DHTs to be more acceptable, appropriate, and accessible to population groups currently at risk of not obtaining the full benefits of digital health.