Abstract Background: Sleep disturbance, fatigue, and anxiety commonly co-occur in adults with cardiovascular disease (CVD) and are strongly associated with impaired quality of life, poor self-care, and increased healthcare utilization. Although these symptoms are well described clinically, the psychosocial mechanisms through which stress is translated into symptom burden remain theoretically fragmented in the literature. Purpose: This paper proposes an integrated conceptual framework that synthesizes the nursing-derived Theory of Unpleasant Symptoms (TOUS) with Lazarus and Folkman’s Stress–Appraisal–Coping model to explain how psychosocial stress contributes to a high-risk symptom cluster in adults with CVD. Approach: Drawing on empirical evidence from cardiovascular nursing, behavioral medicine, and psychophysiology, the integrated framework positions perceived stress and anxiety as antecedents that shape cognitive appraisal and coping responses. Coping quality is conceptualized as a key mediator linking psychosocial stress to downstream symptoms, particularly sleep disturbance and fatigue, while social support functions as a moderating resource that buffers these pathways. Physiological plausibility is discussed through autonomic nervous system and hypothalamic–pituitary–adrenal axis dysregulation, providing a biopsychosocial bridge between appraisal-driven coping and symptom expression. Implications: By uniting symptom science with transactional stress processes, this framework advances a mechanism-focused approach to understanding symptom burden in CVD. It offers clear guidance for nursing assessment, intervention development, and analytic strategies, including mediation and moderation testing using structural equation modeling. The model supports a shift from fragmented symptom management toward upstream, psychosocially informed nursing interventions targeting appraisal, coping, and social resources to improve sleep, functional outcomes, and quality of life in adults with cardiovascular disease.