Background: Social determinants of health (SDOH) can predispose underserved communities to poor cancer outcomes. The CDC has created a Social Vulnerability Index (SVI) score for US counties that integrates four SDOH: socioeconomic status, household composition & disability, minority status & language, and housing type & transportation. Scores range from 0 to 1, with higher values signifying more vulnerability. SVI is a significant determinant of overall mortality, but its association with cancer mortality is unclear. This study aimed to investigate if there is a relationship between SVI and cancer mortality. Methods: CDC WONDER (Wide-Ranging Online Data for Epidemiological Research) was used to estimate age-adjusted mortality rates per 100,000 person-years with 95% CIs for adults > 18 years of age from 3,030 (96%) US counties between 2014-2018 for a composite of three cancers (lung, breast, and colon cancer), individual cancer subtypes, and demographic groups (sex, ethnicity/race, urban/rural classification). Age-adjusted mortality rates were compared across SVI quartiles: 1st (least vulnerable) to 4th (most vulnerable). Linear regression was used to identify the association between the 4th vs. 1st SVI quartile and the odds of being above the median mortality rate for composite cancers, individual cancer subtypes, and demographic groups. Results: Overall, age-adjusted composite cancer mortality rate per 100,000 person-years was 122.9 (lung cancer 82.8, breast cancer 38.1, colon cancer 21.9). The largest concentration of most vulnerable US counties and composite cancer mortality was in the southeastern US. Age-adjusted composite cancer mortality rates increased from 1st to 4th SVI quartiles. Counties in the 4th SVI quartile vs. 1st SVI quartile were significantly more likely to be above the median mortality rate for composite cancer (OR 6.46 [95% CI, 5.16 - 8.08]), lung cancer (6.88 [5.46 - 8.66]), breast cancer (2.77 [2.17 - 3.54]), and colon cancer (6.20 [4.82 - 7.97]). Among all races, non-Hispanic Black adults in the 4th SVI quartile vs. 1st SVI quartile were significantly more likely to be above the median mortality rate for composite cancer (OR 9.46 [95% CI, 6.19 - 14.4]), lung cancer (13.8 [7.87 - 24.1]), breast cancer (5.53 [3.16 - 9.68]), and colon cancer (6.34 [3.69 - 10.9]). Moreover, rural counties in the 4th SVI quartile vs. 1st SVI quartile were between 2- to 8-times more likely to be above the median mortality rate for composite cancer and individual cancer subtypes. Conclusions: This study highlights the most socially vulnerable US counties have higher cancer mortality rates than the least vulnerable US counties. Furthermore, non-Hispanic Black adults and rural counties in the most socially vulnerable category have higher cancer mortality rates than those in the least socially vulnerable category. Additional work is needed to understand how SVI can be used for better resource allocation to help mitigate cancer mortality.