Long non-coding RNA HOX transcript antisense RNA (HOTAIR) is involved in human tumorigenesis and dysregulated in hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HOTAIR functions in HCC are not well understood. Here, an integrated RNA sequencing transcriptomic and quantitative proteomic analysis were employed to systematically explore the regulatory role of HOTAIR in HCC. A total of 673 transcripts and 298 proteins were identified to be dysregulated after HOTAIR inhibition. Bioinformatics studies indicated that the differentially expressed genes (DEGs) and proteins (DEPs) are involved in many biological processes, especially cancer-related signalling pathways.