The association between health-related role limitations in the mental and physical subdomains and clinical status (i.e., chronic disease and comorbid depressive symptoms) is mediated by health-promoting behaviors. To enhance health-promoting behaviors in adults with chronic disease, it is necessary to identify item-level associations among targets of health-related monitoring and management. Therefore, the current study used a network approach to examine associations among health-related role limitations, depressive symptoms, existential well-being, socioeconomic position, and health-promoting behavior in adults with chronic disease. A total of 535 adults (mean ± SD age = 62.9 ± 11.9 years; males, n = 231, females, n = 304) who were regularly visiting an outpatient clinic for chronic disease treatment participated in this cross-sectional study. Data on participant demographics, chronic disease diagnoses, socioeconomic status, health-related role limitations (12-item short form survey scores), depressive symptoms (patient health questionnaire-9 scores), existential well-being (scores for four items of the McGill quality of life questionnaire-Revised), and health-promoting behavior (Healthy Habits Questionnaire scores) were acquired. “Undirected regularized partial correlations” and “directional joint probability distributions” among these variables were calculated using a mixed graphical model (MGM) and directed acyclic graph (DAG). In the MGM, the most influential nodes were emotional well-being, feelings of failure, and health-related limitations affecting usual role and physical activities. According to both the MGM and DAG, the relationship between emotional well-being and feelings of failure mediated the relationships of health-related role limitations with concentration difficulty and suicidal ideation. A positive mindset was dependent on the probability distributions of suicidal ideation, controllability of life, and positive self-image. Both the meaning of life and a positive mindset had direct associations with proactive living. Specifically, proactive living was associated with a balanced diet, regular exercise, volunteering in the community, and nurturing intimacy in social interactions. The meaning and controllability of life in individuals with chronic diseases could mediate the relationships of health-promoting behavior with health-related limitations related to usual role activities, physical activities, and depressive symptoms. Thus, interventions targeting health-promoting behaviors should aim to enhance the meaning and controllability of life (as it pertains to limitations in usual role and physical activities), as well as promote proactive screening and timely psychiatric treatment of depressive symptoms including feelings of failure, concentration difficulties, and suicidal ideation.