Zinc finger CCHC-type containing 4 (ZCCHC4), RNA binding protein, has been reported to mediate rRNA methylation and affect tumor cell proliferation. However, the role of ZCCHC4 in the regulation of osteosarcoma (OS) remains unknown. ZCCHC4 was highly expressed in OS tissues and cell lines. Overexpression or silencing of ZCCHC4 promoted or inhibited cell proliferation, epithelial-mesenchymal transition (EMT), and motility. Additionally, we proved that ZCCHC4 facilitates OS progression through upregulating integrin β1 (ITGB1). In the animal model, ZCCHC4 knockdown reduced OS tumor growth and metastases in vivo. Our findings showed that ZCCHC4 promoted the progression of OS through upregulating ITGB1 and suggested that inhibition of ZCCHC4 could be a novel therapeutic strategy for OS.