Introduction: Chronic illnesses such as coronary heart disease, hypertension and diabetes mellitus are the main causes of death worldwide. Additionally, previous research has discovered that fatigue commonly associated with chronic illness impairs this population’s health-related quality of life (HRQoL), and self-efficacy is critical for self-management. Thus, this study aimed to investigate the association between fatigue and self-efficacy with HRQoL in patients with chronic illness. Methods: We conducted quantitative cross-sectional research using a sample of 160 patients from a public hospital in Klang Valley, Malaysia. Self-efficacy, fatigue, and HRQoL were assessed using a self-administered questionnaire that included the Self-Efficacy Questionnaire and the Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-F), respectively. Results: The mean overall score for HRQoL is 79.91 (SD=13.67), fatigue is 35.28 (SD=7.44), whereas the mean self-efficacy score is 37.93 (SD=9.17). There is a positive correlation between HRQoL with fatigue (r = 0.810, p<0.001) and self-efficacy (r = 0.66, p<0.001). Multiple regression analysis found that sociodemographic characteristics (age, gender, income levels and living area), fatigue and self-efficacy explained 69.5% of variances in HRQoL. Meanwhile, income levels, fatigue and self-efficacy were significant predictors for HRQoL. Conclusion: Fatigue and self-efficacy are among the factors that influence HRQoL among patients with chronic illness. The findings indicated that health practitioners should develop a systematic intervention to prevent fatigue, promote patients’ self-efficacy and HRQoL.