Long non-coding RNAs (lncRNAs) are transcripts that are >200 nucleotides, but with no open reading frame. An increasing number of lncRNAs have been identified following the development of second-generation sequencing technologies, and they have since become a research hotspot. Functionally, they play a vital role in tumor progression, including in tumor proliferation, migration, invasion, apoptosis and acquisition of drug resistance. They regulate gene expression primarily through interaction with DNA, RNA and proteins at the epigenetic, transcriptional and post-transcriptional levels. Endogenous hypoxia-inducible factor 1 alpha antisense RNA 2 (lncRNA HIF1A-AS2) is aberrantly expressed and involved the development/progression of various types of tumors, such as bladder cancer, glioblastoma, breast cancer and osteosarcoma. It plays a vital role in the proliferation, apoptosis, migration, invasion and epithelial-mesenchymal transformation of various tumor cells. This review summarizes the current body of knowledge on the biological functions and related molecular mechanisms of lncRNA HIF1A-AS2 in the development/progression of human tumors and other diseases.