Introduction Few studies have examined the effects of racial segregation on colorectal cancer (CRC) outcomes, and none has determined whether rurality moderates the effect of racial segregation on CRC mortality. We examined whether the effect of segregation on CRC mortality varied by rurality in the Mississippi Delta Region, an economically distressed and historically segregated region of the United States. Methods We used data from the US Census Bureau and the 1999–2018 Surveillance, Epidemiology, and End Results (SEER) program to estimate mixed linear regression models in which CRC mortality rates among Black and White residents in Delta Region counties (N = 252) were stratified by rurality and regressed on White–Black residential segregation indices and 4 socioeconomic control variables. Results Among Black residents, CRC mortality rates in urban counties were a function of a squared segregation term (b = 162.78, P = .01), indicating that the relationship between segregation and CRC mortality was U-shaped. Among White residents, main effects of annual household income (b = 29.01, P = .04) and educational attainment (b = 34.58, P = .03) were associated with CRC mortality rates in urban counties, whereas only annual household income (b = 19.44, P = .04) was associated with CRC mortality rates in rural counties. Racial segregation was not associated with CRC mortality rates among White residents. Conclusion Our county-level analysis suggests that health outcomes related to racial segregation vary by racial, contextual, and community factors. Segregated rural Black communities may feature stronger social bonds among residents than urban communities, thus increasing interpersonal support for cancer prevention and control. Future research should explore the effect of individual-level factors on colorectal cancer mortality.