The Centers for Disease Control and Prevention created the Social Vulnerability Index (SVI) for the purpose of allocating resources in times of emergency based on social determinants of health (SDOH). The purpose of this systematic review was to evaluate how the SVI tool has been applied in health care literature focused on health in the United States (US). A systematic literature review was conducted in 7 research databases with an 11-year time frame reflecting the launch of SVI, with the last search completed on September 29, 2022. Studies were included that involved humans, health, SVI, and conducted in the US. Articles were excluded if the SVI was used in COVID-19, disaster, pandemic, environment, or hazards. A total of 47 articles were included in the systematic review. The majority of studies analyzed individual/population health outcomes in clinical, surgical, mortality, or health promotion areas. The majority of studies showed a relationship between neighborhood-level SDOH and health outcomes. Study authors reported strengths, limitations, and recommendations of the SVI tool. A potential limitation of the study was the exclusion of studies that used the SVI related to disaster. The SVI represents a powerful tool to assess neighborhood-level SDOH and examine upstream drivers health outcomes with direct implications for research, policy, and practice.