Background <p>Stroke survivors experience multidimensional symptom burdens that impair quality of life. However, existing interventions addressing the overall symptom burden of stroke survivors remain limited, and the efficacy of nurse‒patient interaction rehabilitation programs for symptom management remains unclear.</p> Objective <p>This study aimed to evaluate the effect of an intervention based on Cox’s interaction model of client health behavior (IMCHB) on reducing symptom burden and improving self-management in stroke survivors.</p> Methods <p>A two-arm, parallel-group, single-blinded, single-center, randomized controlled trial was conducted with 41 participants per group. The intervention based on Cox’s IMCHB included six phases: (1) program overview (week 1), (2) identification of symptoms (week 2), (3) personalized symptom management codesign through clinical assessments (weeks 3–6), and (4) nurse-guided behavioral intensification with goal reinforcement (weeks 7–9), followed by a wrap-up session (week 10). Outcomes were assessed at baseline (T₀), immediately post-intervention (T₁), and 12 weeks follow-up (T₂) via generalized estimating equation models. This study adhered to the CONSORT 2010 guidelines.</p> Results <p>The nurse-led intervention demonstrated significant benefits across key outcome areas. Specifically, significant improvement was observed in the Southampton Stroke Self-Management Questionnaire at 12 weeks follow-up (<i>β</i> = 8.07, 95% CI: 1.13–15.02, <i>P</i> = 0.023). At the 12 weeks follow-up, participants in the intervention group reported significantly fewer problems regarding secondary prevention (<i>OR</i> = 7.31, 95% CI: 1.90–28.10, <i>P</i> = 0.004), activities of daily living (<i>OR</i> = 7.45, 95% CI: 2.51–22.14, <i>P</i> &lt; 0.001), and emotion (<i>OR</i> = 8.11, 95% CI: 2.64–24.88, <i>P</i> &lt; 0.001). Rehabilitation participation increased significantly both immediately post-intervention (<i>β</i> = 1.21, 95% CI: 0.66–1.76, <i>P</i> &lt; 0.001) and 12 weeks (<i>β</i> = 0.95, 95% CI: 0.21–1.69, <i>P</i> = 0.011). Finally, stroke-specific quality of life showed significant improvement both immediately post-intervention (<i>β</i> = 35.18, 95% CI: 16.09–54.27, <i>P</i> &lt; 0.001) and at 12 weeks follow-up (<i>β</i> = 42.52, 95% CI: 21.92–63.11, <i>P</i> &lt; 0.001).</p> Conclusion <p>The intervention based on Cox’s IMCHB effectively enhances self-management in stroke survivors and reduces multidimensional symptom burden through structured nurse‒patient interactions. By integrating evidence-based support, emotional reinforcement, and shared decision-making, it provides a framework centered on nurse‒patient interactions for holistic stroke rehabilitation. Future research should validate long-term efficacy and explore symptom burden through network analysis.</p> Registration <p>Chinese Clinical Trial Registry (ChiCTR2400092947). Recruitment: Jan to April 2024. [Registration date 2024/11/26 (Retrospectively registered)].</p>