OBJECTIVES: This study aimed to examine the multiple mediation effects of activities of daily living and social isolation on the relationship between physical symptoms and loneliness in patients with heart failure. DESIGN: We adopted a cross-sectional descriptive survey. SETTING AND PARTICIPANTS: A total of 303 patients with heart failure were recruited at 2 general hospitals in China from November 2019 to December 2020. METHODS: Information on loneliness was assessed using the Loneliness Scale of the University of California at Los Angeles (version 3), physical symptoms were evaluated using the Symptom Status Questionnaire-Heart Failure, the Activity of Daily Living Scale was used to evaluate activities of daily living, the Lubben Social Network Scale was used to measure social isolation. The serial mediation model was examined using PROCESS macro in SPSS. RESULTS: Of the 303 patients, 66.7% experienced mild loneliness and 21.8% experienced moderate or severe loneliness. Multiple mediation analysis showed that physical symptoms had a direct effect on loneliness (effect = 0.210; 95% confidence interval (CI) 0.099-0.320) and the link between physical symptoms and loneliness through 3 indirect pathways: (1) activities of daily living (effect = 0.043; 95% CI 0.006‒0.086), accounting for 20.48% of the total effect; (2) social isolation (effect = 0.060; 95% CI 0.005‒0.120), accounting for 28.57% of the total effect; and (3) activities of daily living and social isolation in series (effect = 0.049; 95% CI 0.024‒0.081), accounting for 23.33% of the total effect. The total mediating effect was 72.38%. CONCLUSIONS AND IMPLICATIONS: Activities of daily living and social isolation sequentially mediated the relationship between physical symptoms and loneliness in patients with heart failure. Therefore, attention to reducing activities of daily living limitations and social isolation may be beneficial to reducing loneliness, apart from alleviating physical symptoms.