Background: Severe dengue is a serious infection associated with cytokine storms. Objectives: This study investigated the roles of platelet-activating factor (PAF), syndecan-1, and matrix metalloprotein-9 (MMP-9) in dengue severity. Study design: Blood samples were collected to confirm the diagnosis of dengue infection, and to assess disease severity. Tests performed included non-structural protein 1 dengue test, immunoglobulin G/immunoglobulin M dengue tests, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and a complete blood count. Patients with dengue infection were classified as having dengue fever or dengue hemorrhagic fever. Results: The median levels of PAF, syndecan-1, and MMP-9 in all patients were 73.27 (14.2–769.1) pg/mL, 5.4 (2–64.3) pg/mL, and 197.8 (95.3–962.8) pg/mL, respectively. The levels of all three biomarkers were significantly higher in the dengue hemorrhagic fever and secondary infection groups; with p values < 0.001. Multivariate analysis revealed that PAF and syndecan-1 levels significantly correlated with the severity of dengue infection. Syndecan-1 had the strongest correlation, with a correlation coefficient of 0.43, whereas PAF had a correlation coefficient of 0.30. Conclusions: PAF and syndecan-1 were both independently associated with severe dengue; however, further longitudinal studies are required to validate their predictive potential. © 2025 The Authors