BACKGROUND: Sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia (SMECE) is a rare thyroid tumor. More and more reports have proposed that sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia is significantly invasive, but its origin and pathogenesis are currently controversial. CASE PRESENTATION: We presented a 42-year-old female of Han ethnicity. She had a 4-year history of thyroid nodules, and mild decrease in thyroid function was observed at the time of surgery. Subsequently, pathological examination revealed typical morphological characteristics of sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia. Compared with surrounding normal thyroid tissues, significant eosinophil infiltration was observed in the tumor stroma. Negative thyroglobulin immunohistochemical staining and uniquely positive expression of tumor protein p63 and cytokeratin 5/6 were detected in tumor cells. No genetic mutation was detected by next-generation sequencing. No extrathyroid invasion, lymph node metastasis, or distant metastasis was found. The patient was alive without evidence of disease after 24 months of follow-up. CONCLUSIONS: The case presentation supported this point that sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia originated from solid cell nests, and eosinophils might play an important role in the tumorigenesis and development of sclerosing mucoepidermoid carcinoma of the thyroid with eosinophilia. In addition, a comprehensive analysis of the previously reported cases from reported literature revealed that age and distant metastasis might be the risk factors affecting prognosis.