Squamous cell carcinoma and papillary thyroid carcinoma simultaneously spreading from the thyroglossal duct remnant (TGDR) is a very rare event. The recognition of this condition allows a correct management and treatment, offering the best chances of cure to the patient. We describe the case of a 42-year-old woman who noticed a right-sided lump in her neck. An ultrasound scan confirmed multiple clusters of enlarged lymph nodes on the right side associated to a pre-hyoidal solid nodule. The thyroid gland was normal. Fine-needle aspiration cytology on two nodes revealed distinct metastases from squamous cell carcinoma and from papillary thyroid carcinoma. A careful screening for other head and neck tumors was negative. She underwent a Sistrunk procedure, total thyroidectomy and right lateral lymphadenectomy with en bloc jugular vein resection. On histology, a 2 cm papillary and a small squamous cell carcinoma of the TGDR were documented, with nodal metastases from both primaries. We report the overall management strategy, treatment and outcome at 26-month follow-up, and a review of the literature.