Purpose: Self-rated health (SRH) is a powerful predictor of health-related outcomes such as morbidity and mortality. Aim of the current study was to examine the role of comorbidity, well-being, functional health, and physical limitations as possible predictors of SRH in diabetes and chronic heart failure (CHF). Methods: Three large samples with persons suffering from diabetes (n = 974), CHF (n = 955), or both diseases combined (n = 934) were analyzed longitudinally over the course of 4 months. To test the mediating effect of comorbidity, well-being, functional health, and physical limitations in association with former and future SRH multiple mediator models were applied. Results: Across all groups emotional well-being was a consistent and powerful determinant of SRH. The effects of functional health and physical limitations on SRH were also significant but varied between diagnostic groups. The number of comorbid diseases did not predict SRH. Conclusion: Emotional well-being and physical health appraisal were strong predictors of SRH. Thus, SRH may be improved by influencing well-being and physical health appraisal via targeted interventions.