Aging is accompanied by many chronic comorbidities and disabilities, and entails medical expenses, which affects the quality of life among older adults. The purpose of this study was to investigate whether the health status of older adults with chronic diseases mediates chronic disease self-management to predict quality of life. Methods: This research adopted a cross-sectional correlation study design. Convenient sampling was performed in outpatient departments commonly visited by older adults in a medical center in Southern Taiwan. The following measures were collected: (1) Physiological measurement: left handgrip, right handgrip, and lower extremities’ muscle strength. (2) Questionnaires: cognitive function was measured by the Alzheimer’s disease (AD)-8 scale, possible frailty with the Kihon Checklist (KCL), functional status with the Barthel Index (BI) and the Lawton and Brody Instrumental Activities of Daily Living (IADL) scales, and self-management for chronic disease and quality of life with the (WHOQOL)-BREF, Taiwan version. Results: Chronic disease self-management is correlated with health status and is directly related to quality of life. Chronic disease self-management also indirectly affects quality of life through health status (cognitive status and risk of frailty), showing that health status partly mediates the correlation between chronic disease self-management and quality of life. Conclusions: A health status feedback system should be introduced in related chronic disease self-management measures for older adults so that they can be aware of their own health status and so that their quality of life is improved. Custom-made nursing interventions are necessary for the reduction in or delay of disability or risk of frailty in older adults, thereby enhancing their quality of life.