• Scientific question : The temporal dynamics in cytokine profiles throughout severe fever with thrombocytopenia syndrome (SFTS) progression, their association with clinical severity, and the modifying effects of demographic factors such as age and sex remain insufficiently delineated, necessitating comprehensive longitudinal analyses. • Evidence before this study: Previous studies highlighted cytokine storms in SFTS pathogenesis but were constrained by small samples and cross-sectional designs, lacking longitudinal, multi-center data on cytokine trajectories and their links to disease severity and patient demographics. • New findings: Our multi-center retrospective analysis (2010–2023) of 287 serum samples from high-incidence regions of China revealed that interleukin (IL)-6, interferon (IFN)-α, IL-8, and IFN-γ-induced protein 10 (IP-10) drove hyperinflammation during the acute phase, while IL-10 moderated immune activation and might promote viral persistence, with prolonged elevation of IL-8 and IP-10 in some patients suggesting heterogeneous recovery pathways. Severe cases exhibited significantly higher IL-10, IFN-γ, IL-6, IFN-α, tumor necrosis factor (TNF)-α, IL-8, and IP-10, highlighting their potential as severity biomarkers. At the same time, sex-based differences showed elevated IFN-γ and IL-8 levels in females, and older patients demonstrateed increased IL-10, IFN-γ, and IFN-α. The acute and recovery phases of SFTS demonstrated dynamic variations in immune regulation, and significant changes also occurred in the correlations between cytokines and antibodies. • Significance of the study: Our decade-long multicenter study provides a comprehensive understanding of the immunopathogenesis of SFTS by systematically delineating the temporal dynamics of cytokine profiles throughout the disease. This work establishes a theoretically robust foundation for further investigations into cytokine-targeted therapeutic strategies and the incorporation of predictive biomarkers into clinical practice, ultimately aiming to refine diagnostic methodologies and enhance clinical management.