Purpose <p>Thyrotoxicosis results from either thyroid hyperfunction, as seen in Graves’ disease, or tissue destruction, as in subacute thyroiditis (SAT). Differential diagnosis is essential but can be challenging, with thyroid scintigraphy traditionally used to distinguish between these types. This study investigates the potential of Contrast-Enhanced Ultrasound (CEUS) to provide a non-invasive alternative for differentiating hyperfunction and destructive thyroid disease.</p> Methods <p>In a prospective study, 42 patients with untreated thyrotoxicosis were evaluated using CEUS to analyze both qualitative and quantitative perfusion parameters.</p> Results <p>Group 1 included 20 patients with Graves’ disease, while Group 2 comprised 22 patients with destructive thyrotoxicosis (SAT, Hashitoxicosis, postpartum thyroiditis, and iatrogenic cases). Significant differences were observed in CEUS parameters between the two groups. Hyperfunction cases showed higher Peak Intensity (PKI), Area Under Curve (AUC), Wash-in AUC (WiAUC), Wash-out AUC (WoAUC), and Mean Time-Intensity Curve (mTIC), while Rise Time (RT) and Time to Peak (TTP) were prolonged in the destruction group. Strong correlations with hyperfunction were observed for PKI, AUC, WoAUC, and mTIC. Optimal cut-off values of AUC &gt; 1991, WoAUC &gt; 1876, and mTIC &gt; 10 achieved 100% sensitivity and specificity for identifying hyperfunction.</p> Conclusion <p>This preliminary study suggests that CEUS, with its quantitative and qualitative assessments, could be a valuable tool in the non-invasive differential diagnosis of thyrotoxicosis, potentially reducing the need for scintigraphy and enabling rapid and accurate treatment decisions.</p>