Background <p>Narcolepsy is often accompanied by depressive and anxiety symptoms, but the underlying immunological mechanisms remain unclear. Inflammatory cytokines may play a role in both disease onset and psychiatric comorbidities. This study aimed to investigate the association between circulating inflammatory cytokines and neuropsychiatric symptoms in paediatric narcolepsy patients, in order to explore the potential role of immune dysregulation in disease pathogenesis and comorbid mood disorders.</p> Methods <p>This cross-sectional study included 78 paediatric narcolepsy patients and 80 age-matched controls. Cytokine levels and lymphocyte subsets were measured using ELISA and flow cytometry. Depression and anxiety symptoms were assessed using the HAMD-24 and HAMA-14 scales. Logistic regression was used to identify immune markers associated with narcolepsy diagnosis, while linear regression assessed their relationships with depressive and anxiety symptoms.</p> Results <p>Compared to healthy controls, paediatric narcolepsy patients exhibited significantly elevated levels of IL-6, IL-2, IL-4, TNF-α, IFN-γ, and IL-17&#xa0;A, alongside reduced IL-10 levels (all <i>P</i> &lt; 0.05). Logistic regression analysis identified IL-6 as an independent risk factor for narcolepsy (OR = 1.46, 95% CI: 1.02–1.93, <i>P</i> = 0.003). Furthermore, IL-6 and the IL-6/IL-10 ratio were positively associated with depressive symptom severity as measured by HAMD-24 scores (<i>P</i> = 0.023 and <i>P</i> = 0.018, respectively). The IFN-γ/IL-4 ratio was independently associated with anxiety symptoms, as reflected by HAMA-14 scores (<i>P</i> = 0.007), after adjusting for confounding variables.</p> Conclusion <p>These findings suggest that pro-inflammatory cytokines, especially IL-6, are involved in the pathophysiology of paediatric narcolepsy and its related depressive and anxiety symptoms. IL-6 may serve as a potential biomarker and therapeutic target for early intervention.</p>