Purpose: Medication non-adherence is a major public health issue. Recent evidence suggests that depression, inadequate social support, and lower levels of self-efficacy are associated with poor medication adherence. However, the mechanism underlying the association among depression, social support, self-efficacy and medication adherence is unclear. This study aims to examine the mediating role of social support and self-efficacy between depression and medication adherence in older patients with coronary heart disease. Patients and Methods: Data were collected from 238 hospitalized older patients with coronary heart disease. Depression, social support, self-efficacy, and medication adherence were assessed using structured questionnaires. A serial multiple mediation model was tested using the PROCESS macro for SPSS. Results: A total of 238 older patients with CHD with a mean age of 70.5 years were involved in this cross-sectional study. Depression was negatively correlated with medication adherence in older patients with coronary heart disease. Social support and self-efficacy were positively associated with medication adherence, and fully mediated the relationship between depression and medication adherence. Three mediation paths were included in the model: (a) social support, (b) chain combination of social support and selfConclusion: Social support and self-efficacy explain the association of depression and medication adherence in older CHD patients and may be the keys target for enhanced intervention to improve medication adherence in older CHD patients with depression.