Menin, encoded by MEN1 gene, has been viewed as a tumor suppressor in several types of tumors, such as insulinoma, parathyroid tumor, and adrenocortical and lung carcinoma. However, its expression and molecular regulation mechanism in osteosarcoma has not been elucidated. Here, our results show menin expression is significantly down-regulated in osteosarcoma tissues, compared with adjacent normal tissues. Besides, we report that MicroRNA-142-3p as a novel target of menin. Up-regulation of MicroRNA-142-3p by menin overexpression inhibits cell proliferation in U2OS and MG63 cells. At the molecular level, MicroRNA-142-3p inhibits the protein expression of FASN through binding to its 3'-untranslated region. Therefore, we elucidate a novel regulation pathway in osteosarcoma cells and suggest a potential therapeutic approach for the tumor therapy.