The long noncoding RNA HOX transcript antisense RNA (HOTAIR) has been reported to be an oncogene that influences tumor cell development and that correlates with prognosis in hepatocellular carcinoma (HCC). Accumulating evidence indicates that autophagy plays a significant role in tumorigenesis and cancer cell survival, but whether HOTAIR modulates autophagy in HCC cells remains unknown. In this study, HOTAIR expression was measured in 54 matched paired HCC tissues and the adjacent non-tumor tissues. HOTAIR was overexpressed in the HCC tissues as compared with the adjacent non-tumor tissues and was associated with tumor size. In vitro assays revealed that the overexpression of HOTAIR promoted the activation of autophagy in HCC cell lines, whereas HOTAIR knockdown suppressed it. Further investigation revealed that overexpressed HOTAIR upregulated autophagy-related 3 (ATG3) and ATG7 expression in HCC cells. In conclusion, HOTAIR, overexpressed in HCC and associated with tumor size, could activate autophagy by increasing ATG3 and ATG7 expression, promoting HCC cell proliferation.