Purpose As the population living with several concurrent chronic conditions or multiple morbidity (MM) increases, understanding how to effectively fit prevention efforts into disease management becomes more important, particularly among rural, underserved populations. Compared to their urban counterparts, rural residents suffer higher rates of disease, receive fewer preventive services, and often live in environments limiting access to optimal medical care. This study describes rural residents’ perceived burdens of disease management and explores the relationship between these burdens, as proxies of individuals’ competing demands, and colorectal cancer screening (CRCS). Methods We conducted a cross‐sectional study, based on telephone survey data from 1,012 Appalachian residents, ages 50‐75, with 1 or more chronic conditions. Measures of perceived MM burdens were developed based on 85 pilot interviews previously undertaken with providers and patients with MM residing in Appalachian Kentucky. Results Many participants (81%) agreed with 1 or more statements indicating perceived burdens of disease management effects on receiving CRCS. A higher percentage of rural (vs nonrural) Appalachians perceived burdens related to physician's recommendation, preparation to colonoscopy, and time management and affordability of both current diseases and screening. These differences did not modify the overall association between perceiving MM as burdensome and forgoing CRCS. The negative effect on CRCS of perceived burdens related to interaction with physician and time management was lower for participants with multiple rather than single morbidity. Conclusion Future research designed to address perceived burdens of MM and improved interaction with health care providers may enhance critical prevention efforts among vulnerable populations.