BACKGROUND: Hypothyroidism (HT) is associated with different comorbidities comprising increased arterial stiffness and decreased flow-mediated dilatation. The exact pathological mechanism of endothelial activation and dysfunction (ED) in HT remains unknown. We conducted a systematic review and meta-analyses to provide an overview of the pathogenesis of ED in HT. METHODS: The literature search was done in February 2024 for studies analyzing traditional and novel circulating biomarkers of ED in patients with HT, including cytokines and chemokines. Random-effect models were used except when no heterogeneity was found. Protocol was registered under the number PROSPERO CRD42024540560. RESULTS: 25 macromolecules and 66 studies were entered into analyses. HT was associated with increased levels of E-selectin, soluble intercellular adhesion molecule-1, osteoprotegerin, and oxidized-LDL ( CONCLUSIONS: The data presented and discussed here highlights the association between HT and soluble biomarkers of ED. Inflammatory mediators released by activated T-cells and macrophages may aggravate local and systemic inflammation, which arouses more inflammation, forming a vicious circle leading to ED.