Purpose: Rural cancer survivors (RCS) have poorer health outcomes and face multiple challenges—older age, and limited transportation, education, income, and healthcare access. Yet, RCS are understudied. The Reach-out to ENhancE Wellness(RENEW) trial, a home-based, diet and exercise intervention among 641 breast, prostate, and colorectal cancer survivors addressed many of these challenges. Methods: We examined whether rural and urban participants differed in their response to the RENEW intervention (e.g., physical functioning, quality-of-life, intakes of fruits and vegetables (F&V) and saturated fat, body mass index(BMI), physical activity, and adverse events). Results: Rural versus urban survivors report significantly more favorable mean (SE) changes in physical functioning [− 0.66 (1.47) v − 1.71 (1.00)], physical health [+ 0.14 (0.71) v − 0.74 (0.50)], and fewer adverse events [1.58 (0.08) v 1.64 (0.06)]. Rural versus urban survivors reported smaller increases in F&Vs [+ 1.47 (0.23) v + 1.56(0.16); p = 0.018], and lower percentages achieved goal behavior for endurance exercise and intakes of F&Vs and saturated fat. Conclusions: The RENEW intervention reduced declines in physical health and functioning among RCS to a significantly greater extent than for urban cancer survivors. All survivors significantly improved intakes of F&V and saturated fat, and endurance exercise; however, lower percentages of rural versus urban survivors met goal suggesting that more intensive interventions may be needed for RCS.