Background. The relationship among comfort, perceived social support, and hope should still be further explored. Clarifying the relationship between the aforementioned variables can enable clinical staff to implement tailored and effective intervention strategies for enhancing the management and quality of care of patients with ischemic stroke. Aim. This study aims to investigate the relationship between comfort, perceived social support, and hope in hospitalized patients with acute ischemic stroke and to explore the mediating effect of perceived social support on comfort and hope. Methods. A correlational cross‐sectional study was performed using an online questionnaire. The study was conducted from January to August 2023 among 572 patients with acute ischemic stroke, and finally 534 valid questionnaires were included in the analysis. The general information questionnaire, Modified Barthel Index, Shortened General Comfort Questionnaire, Perceived Social Support Scale, and Herth Hope Index were utilized for investigation. Mediation analysis was performed by structural equation modelling. Indirect effects were evaluated through bootstrapping. Data analysis was performed using the statistical program packages, namely, SPSS 29.0 and AMOS 24.0. Results. The comfort, perceived social support, and hope scores of patients with acute ischemic stroke were 94.1 (11.92), 72.74 (10.26), and 40.55 (4.99), respectively. The participants’ hope was positively related to comfort (r = 0.531, p < 0.001) and perceived social support (r = 0.589, p < 0.001). Perceived social support exerts a partial mediating role between comfort and hope, and the mediating effect was 0.159 (95% CI [0.117, 0.210]), accounting for 25.0% of the total effect. Conclusion. We reported that comfort—directly and indirectly—exerts a positive impact on hope. Particularly, perceived social support enhances the impact of comfort on hope; perceived social support mediates the relationship between comfort and hope. Clinical staff should correctly understand the relationship among the three variables; they should effects targeted strategies to enhance patient comfort and social support, thereby increasing the hope level among ischemic stroke patients and bolstering confidence in disease management. Implications for Nursing Management. This study demonstrates that comfort and perceived social support serve as protective factors for hope among ischemic stroke patients. This observation provides evidence supporting the optimization of management for ischemic stroke patients from the perspectives of the cognitive adaptation theory and comfort theory. The findings of this study contribute to a more optimal understanding among clinical caregivers regarding the mechanisms underlying the relationship between comfort, social support, and hope, and it facilitates the adoption of effective intervention strategies for promoting the psychological management of ischemic stroke patients and enhancing patient care quality.