Objective To explore the role of electronic health literacy and social support in the chain mediator effects between depression and health-related quality of life in patients with chronic diseases, so as to make reference for formulating targeted intervention measures to enhance health-related quality of life of patients with chronic diseases for the elderly. Methods A total of 1,545 elderly patients with chronic diseases were selected by multi-stage stratified cluster. General data questionnaire, Electronic Health Literacy Scale, Hospital Anxiety and Depression Scale, Social support Rating Scale and European five-dimension Health Scale were used to investigate. Results The median depression score of elderly patients with chronic diseases was 9(8,11), and health-related quality of life score was 0.784(0.533,0.897). There was a negative correlation between depression and electronic health literacy, social support and health-related quality of life (all P<0.05). According to the mediating effect test, electronic health literacy and social support played a chain mediating role in depression and health-related quality of life. The mediating effect accounted for 15.6% of the total effect. Conclusion Depression not only directly affects health-related quality of life in elderly patients with chronic diseases, but also indirectly predicts health-related quality of life through the mediating effects of electronic health literacy and social support.