Xanthogranulomatous inflammation (XGI) is an uncommon destructive chronic inflammatory process mainly occurring in the kidney and gallbladder, characterized by the accumulation of foamy histiocytes, multinucleated giant cells (Touton type), cholesterol clefts and chronic inflammatory cells. The head and neck region is an uncommon site for XGI. This type of inflammatory reaction has been defined in branchial cleft cyst, salivary gland tumors following fine-needle aspiration biopsies, Rathke's cleft cyst in the pituitary gland, and colloid cyst in the 3rd ventricle. We present herein a unique case of ruptured thyroglossal duct cyst leading to XGI, characterized by an infiltrative subcutaneous central neck lesion, clinically mimicking a thyroid carcinoma. In addition, we also summarize current insights into the pathogenesis of XGI in the head and neck region.