Introduction: The adult population is increasingly experiencing one or more chronic illnesses and living with such conditions longer. The Chronic Disease Self-Management Program (CDSMP) helps participants cope with chronic disease-related symptomatology and improve their health-related quality of life. Nevertheless, the long-term effectiveness of this evidence-based program on older adults as compared to the middle-aged populations has not been examined in a large-scale, national rollout. Method: We identified baseline characteristics of CDSMP participants aged 65 years or older (n = 687, M = 74.8 years) in the National Study of CDSMP from 2010 to 2012. Comparisons were made to middle-aged participants aged 50 to 64 (n = 325, M = 58.3 years). Assessments were conducted at baseline and 12-month follow-up. Linear and generalized linear mixed models were performed to assess changes in primary and secondary outcomes, controlling the key sociodemographics and number of chronic conditions. Results: All primary outcomes (i.e., social/role activities limitation, depression, communication with doctors) significantly improved in both the older and middle-aged cohorts. Although improvements in illness symptomatology (e.g., fatigue, pain, shortness of breath, and sleep problems) were similar across both cohorts, only the middle-aged cohort benefitted significantly in terms of overall quality of life and unhealthy mental health days. Effect sizes were larger among the middle-aged population who were also more likely to enter the program in poorer health and be from minority backgrounds. Conclusions: The current study documented improved health outcomes but more so among the middle-aged population. Findings suggest the importance of examining how age and interacting life circumstances may affect chronic disease self-management. [This article is part of an open access supplement "Fostering Engagement and Independence: Opportunities and Challenges for an Aging Society," published in SOPHE's "Health Education & Behavior." This supplement was supported by funding provided by the Centers for Disease Control and Prevention's (CDC) National Center for Chronic Disease Prevention and Health Promotion, Healthy Aging Program (Cooperative Agreement #U38HM000454) via the Association of State and Territorial Health Officials, and from a grant provided by the Retirement Research Foundation.]