US health expenditures have been growing at an unsustainable rate, while health inequities and poor outcomes persist. Targeting social determinants of health (SDOH) may contribute to identifying and controlling health care expenditures. To determine whether SDOH are associated with US health care expenditures by Medicare, Medicaid, and private insurers. Cross-sectional study of adults, representing the US civilian, noninstitutionalized population with Medicare, Medicaid, or private coverage, from the 2021 Medical Expenditure Panel SDOH Survey. Data analysis was conducted from October 2023 to April 2024. SDOH as individual-level, health-related social needs categorized by Healthy People 2030 domains: (1) educational access and quality, (2) health care access and quality, (3) neighborhood and built environment,(4) economic stability, and (5) social and community context. The primary outcome was health care expenditures (US dollars) by Medicare, Medicaid, and private insurers. A 2-part econometric model (probit regression model and generalized linear model with gamma distribution) was used. Among the 14 918 insured adults in the analytic sample (mean [SD] age, 52.5 [17.9] years; 8471 female [56.8%]), the majority had middle to high family income (10 524 participants [70.5%]) and were privately insured (10 227 participants [68.5%]). Annual median (IQR) expenditure was $1648 ($389-$7126) for Medicaid, $3643 ($1321-$10 519) for Medicare, and $1369 ($456-$4078) for private insurers. Educational attainment and social isolation were associated with Medicaid expenditures. Medicaid beneficiaries with a high school diploma or general educational development certificate had on average (mean difference) $2245.39 lower annual Medicaid expenditures (95% CI, -$3700.97 to -$789.80) compared with beneficiaries with less than high school attainment. Compared with those who never felt isolated, Medicaid beneficiaries who often felt isolated had on average $2706.94 (95% CI, $1339.06-$4074.82) higher annual Medicaid expenditures. Health care access, built environment, and economic stability were associated with Medicare expenditures. Medicare beneficiaries living in neighborhoods with lower availability of parks had on average $5959.27 (95% CI, $1679.99 to $10 238.55) higher annual Medicare expenditures. Medicare beneficiaries who were very confident in covering unexpected expenses had on average $3743.98 lower annual Medicare expenditures (95% CI, -$6500.68 to -$987.28) compared with those who were not confident. Medical discrimination and economic stability were associated with private expenditures. Private insurance beneficiaries who experienced medical discrimination had on average $2599.93 (95% CI, $863.71-$4336.15) higher annual private expenditures compared with those who did not. Private beneficiaries who were contacted by debt collections in the past year had on average $2033.34 (95% CI, $896.82 to $3169.86) higher annual private expenditures compared with those who were not contacted. In this cross-sectional study of 14 918 insured adults, individual-level SDOH were significantly associated with US health care expenditures by Medicare, Medicaid, and private insurers. These findings may inform health insurers and policymakers to incorporate SDOH in their decision-making practices to identify and control health care expenditures, advancing health equity.