The syndemic model exemplifies the effect of the clustering of health conditions which are intensified by socioecological factors that result in worse outcomes among vulnerable populations. The ongoing COVID-19 pandemic has demonstrated varying health outcomes against a backdrop of distinctive structural contexts. A holistic view of the factors responsible for the wavering health outcomes at the individual, family and community levels point to the interplay between biological and socioecological factors. Studies have shown the role the biological interactions of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with existing communicable and non-communicable diseases play in increasing vulnerability to worse health outcomes. A similar dynamic has been demonstrated by the biological interactions of the virus with social determinants of health and political factors. Together, these factors synergistically create a spectrum of possible outcomes, making some individuals and populations more vulnerable to worse outcomes than others. Though several COVID-19 studies have been conducted, there are relatively few studies which explore the disease from a syndemic model. This leaves a research gap in the study of the effects of the disease on existing diseases in the host system, as well as social, environmental, and political factors that may increase the risk of individuals and populations to clustered disease effects. Researchers are urged to view the COVID-19 pandemic through a syndemic lens, and design and implement studies based on this perspective. In addition, we recommend the development and implementation of a global syndemic framework by international bodies, which will be adaptable at national and subnational levels for the conduct COVID-19 related studies. These could provide better understanding of the virus and the factors that lead to the clustering effects which have both direct and indirect impact on health outcomes.