As an oncogenic driver, lysine-specific demethylase 5A (KDM5A) participates in regulating numerous tumor progression-related processes. Moreover, KDM5A functions as a histone demethylase, modulating the expression levels of its target genes by adjusting methylation levels. However, the underlying molecular mechanism of KDM5A in osteosarcoma remains elusive. To elucidate this mechanism, specifically how the KDM5A /Homeobox A5 (HOXA5) axis regulates osteosarcoma progression, we measured the expression levels of KDM5A and HOXA5 genes using reverse transcription-quantitative real-time PCR. The correlation between HOXA5 and KDM5A was analyzed via Pearson correlation analysis and further validated through chromatin immunoprecipitation-quantitative real-time PCR. Immunohistochemistry was conducted to determine the number of KDM5A-or HOXA5-positive cells present in osteosarcoma tissues. Additionally, Western blot analysis was utilized to quantify the protein levels of KDM5A, HOXA5, di- and tri-methylation of lysine 4 on histone H3, and β-catenin. Colony formation assays, wound healing assays and flow cytometry were used to detect cell proliferation, migration and apoptosis. The factors associated with the five-year survival rate of patients were analyzed. Our results illustrated that KDM5A was up-regulated in osteosarcoma and associated with a poor prognosis; KDM5A knockdown inhibited osteosarcoma cell proliferation and migration and promotes apoptosis. Subsequently, KDM5A knockdown induced HOXA5 expression by promoting di- and tri-methylation of lysine 4 on histone H3 demethylation, and HOXA5 overexpression inhibited osteosarcoma cell proliferation and migration, and promoted apoptosis by inhibiting the Wnt/β-catenin pathway. We finally proved that HOXA5 silence weakened the inhibitory effect of sh- KDM5A on osteosarcoma proliferation and migration and promoted apoptosis via activating Wnt/β-catenin pathway in vivo and in vitro. Our study demonstrated that the KDM5A /HOXA5 axis regulates osteosarcoma progression by activating the Wnt/β-catenin pathway.