Long non-coding RNAs (LncRNAs) are acknowledged as crucial regulators in tumorigenesis and tumor progression. In this study, we explored the mechanism and function of lncRNA HCP5 in osteosarcoma (OS). At first, five lncRNAs were chosen from GeneCard and subjected to qRT-PCR examination. The results indicated that HCP5 was significantly overexpressed in four OS cell lines. Northern blot assay further proved the higher expression of HCP5 in OS cell lines. To identify the biological role of HCP5 in OS, we silenced the expression of HCP5 in U2OS and MG-63 cells which possessed the highest level of HCP5. CCK-8 and colony formation assay revealed the inhibitory effect of HCP5 knockdown on cell proliferation. Cell apoptosis was found to be increased in cells transfected with sh-HCP5#1. Moreover, cell invasion and epithelial-mesenchymal transition (EMT) were reversed by the silencing of HCP5. The results of functional assays showed that HCP5 acted as an oncogene in osteosarcoma. Mechanically, HCP5 was found to be activated by the transcription factor SP1. Finally, rescue assays were conducted to demonstrate the function of SP1/HCP5 axis in osteosarcoma. In conclusion, we confirmed that SP1-induced upregulation of long non-coding RNA HCP5 promotes the development of osteosarcoma.