Purpose Multiple chronic illnesses, such as those associated with advanced age, are leading causes of poor health, disability, death, and high healthcare expenditures. Tele‐homecare is a novel method for providing home care to patients with chronic illnesses. The purpose of this study was to evaluate the effectiveness of an integrated nurse‐led tele‐homecare program for patients with multiple chronic illnesses and a high risk for readmission. Design A randomized controlled trial. Methods Two hundred patients from a regional hospital who were scheduled to receive home care after discharge were randomly assigned to the intervention group (n = 100) or the control group (n = 100). The patients in the intervention group participated in an integrated tele‐homecare program. For outcome evaluation, primary outcomes included the number of emergency department (ED) visits as well as readmittance and mortality. Secondary outcomes included patients’ medication adherence, activities of daily living, health status, and quality of life (QOL). Data were collected at three time points: pretest baseline (T0), 3 months after intervention (T3), and 6 months after intervention (T6). A generalized estimating equation model was used to compare changes and evaluate the effect of differences between the two groups over time. Findings For primary outcome evaluation, we found that the tele‐homecare program significantly reduced mortality and ED visits, whereas no significant effect on readmission was observed. For secondary outcome evaluation, patients’ QOL indicated significant improvement. Conclusions and Clinical Relevance The nurse‐led tele‐homecare program involves daily 24‐hr remote monitoring and surveillance. In this study, the system detected patients’ physical changes early and provided timely and appropriate management, consequently reducing ED visits and mortality. Additionally, it improved patients’ QOL. On the basis of our findings, nurses’ independent roles and functions revealed that the effectiveness of this nurse‐led tele‐homecare program strengthened the care of patients with multiple chronic illnesses.