Substantial gaps in national healthcare spending and disparities in cancer mortality rates are noted across counties in the US. In this cross-sectional analysis, we investigated whether differences in local county-level social vulnerability impacts cancer-related mortality. We linked county-level age-adjusted mortality rates (AAMR) from the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research database, to county-level Social Vulnerability Index (SVI) from the CDC Agency for Toxic Substances and Disease Registry. SVI is a metric comprising 15 social factors including socioeconomic status, household composition and disability, minority status and language, and housing type and transportation. AAMRs were compared between least and most vulnerable counties using robust linear regression models. There were 4 107 273 deaths with an overall AAMR of 173 per 100 000 individuals. Highest AAMRs were noted in older adults, men, non-Hispanic Black individuals, and rural and Southern counties. Highest mortality risk increases between least and most vulnerable counties were noted in Southern and rural counties, individuals aged 45-65, and lung and colorectal cancers, suggesting that these groups may face highest risk for health inequity. These findings inform ongoing deliberations in public health policy at the state and federal level and encourage increased investment into socially disadvantaged counties.