ImportancePublicly available, US Census–based composite measures of socioeconomic disadvantage are increasingly being used in a wide range of clinical outcomes and health services research. Area Deprivation Index (ADI) and Social Vulnerability Index (SVI) are 2 of the most commonly used measures. There is also early interest in incorporating area-level measures to create more equitable alternative payment models.ObjectiveTo review the evidence on the association of ADI and SVI with health care spending, including claims-based spending and patient-reported barriers to care due to cost.Evidence ReviewA systematic search for English-language articles and abstracts was performed in the PubMed, Web of Science, Embase, and Cochrane databases (from inception to March 1, 2023). Peer-reviewed articles and abstracts using a cross-sectional, case-control, or cohort study design and based in the US were identified. Data analysis was performed in March 2023.FindingsThis review included 24 articles and abstracts that used a cross-sectional, case-control, or cohort study design. In 20 of 24 studies (83%), ADI and SVI were associated with increased health care spending. No association was observed in the 4 remaining studies, mostly with smaller sample sizes from single centers. In adjusted models, the increase in spending associated with higher ADI or SVI residence was $574 to $1811 for index surgical hospitalizations, $3003 to $24 075 for 30- and 90-day episodes of care, and $3519 for total annual spending for Medicare beneficiaries. In the studies that explored mechanisms, postoperative complications, readmission risk, and poor primary care access emerged as health care system–related drivers of increased spending.Conclusions and RelevanceThe findings of this systematic review suggest that both ADI and SVI can play important roles in efforts to understand drivers of health care spending and in the design of payment and care delivery programs that capture aspects of social risk. At the health care system level, higher health care spending and poor care access associated with ADI or SVI may represent opportunities to codesign interventions with patients from high ADI or SVI areas to improve access to high-value health care and health promotion more broadly.