Diffuse thyroid lipomatosis is a rare histopathological condition of unknown etiology, characterized by diffuse fatty infiltration of the thyroid stroma, which can result in diffuse goiter with compressive symptoms. We report a case of a 46-year-old man with 1-year history of progressive goiter enlargement with compressive symptoms. Imaging studies revealed multiple coalescent nodules. The patient underwent surgery, and the microscopic appearance revealed a diffuse infiltration of thyroid stroma by mature adipose tissue with associated amyloid deposition. A final diagnosis of diffuse lipomatosis of the thyroid gland was established. This patient represents one of the few reported cases of diffuse lipomatosis with coexisting deposition of amyloid protein of the thyroid gland and contributes to the better understanding of this extremely rare condition.