Osteosarcoma is the most common primary bone malignancy; however, the molecular mechanisms of development are not well understood. Progestin and AdipoQ receptors (PAQR3), a protein specifically localized in the Golgi apparatus, was recently characterized as a new tumor suppressor. Little is known about the expression and function of PAQR3 in osteosarcoma. Here, we showed that PAQR3 was downregulated in osteosarcoma tissues compared with the adjacent normal regions in 80 paired samples. Moreover, lower levels of PAQR3 were associated with metastasis in clinical osteosarcoma patients. In addition, overexpression of PAQR3 in the osteosarcoma cell line MG-63 inhibited cell proliferation, migration, and invasion by promoting ERK phosphorylation. Taken together, our results indicated that PAQR3 might act as a tumor suppressor in osteosarcoma, providing a novel diagnostic and therapeutic option for human osteosarcoma in the future.