LncRNA HOXA11-AS functions as regulator of tumorigenesis of several human cancers. The present study was intended to explore its regulatory control in human skin cancer with emphasis on understanding the underlying molecular mechanism. The results showed significant ( < 0.05) upregulation of lncRNA HOXA11-AS transcript levels in human skin cancer tissues and cell lines. The knockdown of HOXA11-AS significantly ( < 0.05) inhibited the proliferation and colony formation of A375 and HMCB skin cancer cells. Flow cytometry showed that HOXA11-AS knockdown triggered arrest of the A375 and HMCB cells at G/M check point of cell cycle by inhibiting the expression of cyclin B1. Additionally, western blot analysis showed that HOXA11-AS knockdown resulted in the deactivation of PI3K/AKT/mTOR signaling pathway. The silencing of HOXA11-AS significantly ( < 0.05) inhibited the migration and invasion of the A375 and HMCB skin cancer cells. This was also accompanied by increase in E-cadherin and decrease in N-cadherin expression. Collectively, the results indicate that lncRNA HOXA11-AS regulates the proliferation, migration and invasion of human skin cancer and may exhibit therapeutic potential in the treatment of skin cancer.