Objective: This study aimed to investigate the correlation between self-care knowledge, psychological well-being, and disease self-management in patients with hypertensive nephropathy, and to assess the effect of psychological well-being as a mediator of self-care knowledge and disease self-management. Methods: This is a cross-sectional study. The 220 patients with hypertensive nephropathy were recruited from a teaching hospital in Taiwan using purposive sampling. The average age was 70.14 (SD = 11.96) years old. Among them, 128 (58.2%) were male and 92 (41.8%) were female. Instruments included a hypertensive nephropathy self-care knowledge scale, the World Health Organization-5 Well-Being Index, and the chronic kidney disease self-management instrument. The mediating effect was determined with linear regression models and the Sobel test. Results: The total explanatory variation of age, systolic blood pressure, psychological well-being, and self-care knowledge on the disease self-management was 27.7%. Psychological well-being was the most important explanatory factor and alone explains 16%. Psychological well-being was a partial mediator of self-care knowledge and quality of life in patients with hypertensive nephropathy, with a total effect of 23.2%. Conclusions: This study showed that older patients with hypertensive nephropathy and those with a higher systolic blood pressure had lower levels of disease self-management. The higher the patients’ self-care knowledge and psychological well-being, the better their disease self-management.