Background: Osteosarcoma (OS) is still a disease with high mortality from malignant tumors in children and adolescents. Due to its poor treatment, this study explored the involvement of lncRNA ZFAS1/microRNA-135a (miR-135a)/ apurinic/apyrimidinic exonuclease 1 (APEX1) axis in the regulation of OS growth and metastasis. Methods: ZFAS1, miR-135a and APEX1 expression in OS tissues and cells were tested by RT-qPCR and western blot analysis. MG63 cells were transfected with sh-ZFAS1, miR-135a mimic or their controls to unearth theirs functions in the proliferation, colony formation, migration, invasion, cycle entry and apoptosis of MG63 cells by MTT and EdU, colony formation assays, flow cytometry, and Transwell assay, severally. The proliferation related factor (Ki-67, CyclinD1), apoptosis related factor (Bax, Bcl-2) and migration related factor (MMP2, MMP9) protein levels were tested. Tumor volume and weight were detected by subcutaneous tumor xenograft in nude mice. Results: Overexpressed ZFAS1 and APEX1, and down-regulated miR-135a existed in OS tissues and cells. Silenced ZFAS1 or elevated miR-135a inhibited colony formation and proliferation, cycle progression, migration and invasion while promoted apoptosis of MG63 cells. Silenced ZFAS1 or elevated miR-135a suppressed tumor volume and weight of OS in vivo. LncRNA ZFAS1 promoted APEX1 expression by competitively binding with miR-135a. Conclusion: This study indicates that silenced ZFAS1 or up-regulated miR-135a restrained migration, proliferation and invasion and promoted apoptosis of OS MG63 cells. This study provides a possible theoretical basis for studying the regulatory mechanism of ZFAS1/miR-135a/APEX1 signaling axis on the growth and metastasis of OS.