Rural disparities in cancer outcomes have been widely evaluated, but limited evidence is available to describe what characteristics of rural environments contribute to the increased risk of poor outcomes. Therefore, this manuscript sought to assess the mediating effects of county characteristics on the relationship between urban/rural status and mortality among patients with cancer, characterize county profiles, and determine at-risk county profiles alongside rural settings. Patients diagnosed with cancer between 2000 and 2016 were assessed using Surveillance, Epidemiology and End Results data linked to the 2010 Rural-Urban Commuting Codes and 2010 County Health Rankings. There were 757,655 patients representing 596 counties (of 3,143 in the U.S.) and 12 states. Mediation analyses, conducted in 2023, estimated the direct contribution of rurality to 5-year all-cause survival and the contribution of the rural effect indirectly through County Health Ranking domains. Latent class analysis and survival models identified county groupings and estimated the hazard of mortality associated with class membership. Rankings for premature death, clinical care, and physical environment resulted in rural patients having 17.9%–20.2% less survival time than urban patients. Of this, 4.1%–12.6% of the total excess risk was mediated by these characteristics. Patients living in rural and high-risk county classes saw higher all-cause mortality than those in urban lower-risk counties (hazard ratio=1.04, 95% CI=1.01, 1.08 and 1.07, 95% CI=1.03, 1.11). Counties with poorer health rankings had increased mortality risks regardless of rurality; however, the poor rankings, notably health behaviors and social and economic factors, elevated the risk for rural counties.