Hepatocellular carcinoma (HCC) has become one of the most common leading causes of cancer-related deaths worldwide. This study investigates the role of lncRNA, SPRY4-IT1 in the development of HCC. Quantitative real-time PCR (qRT-PCR) was performed and the results showed that SPRY4-IT1 expression was up-regulated in HCC tissues and high expression of SPRY4-IT1 was associated with poor 5-year overall survival in the HCC patient cohort. Clinicopathological analysis showed that the expression of SPRY4-IT1 was significantly correlated with TNM stage in HCC patients. In vitro CCK-8 assay, colony formation assay, cell invasion and migration assays demonstrated that knock-down of SPRY4-IT1 suppressed cell proliferation, colony formation, cell invasion and migration in HCC cells. Flow cytometric analysis showed that knock-down of SPRY4-IT1 induced cell cycle arrest at G0/G1 phase and induced apoptosis. In addition, knock-down of SPRY4-IT1 also suppressed the mRNA and protein expression of estrogen-related receptor α (ERRα). Similarly, knock-down of ERRα inhibited cell proliferation, colony formation, cell invasion and migration in HCC cells. More importantly, ERRα overexpression antagonized the effects of SPRY4-IT1 knock-down on cell proliferation, colony formation, cell invasion and migration in HCC cells. Taken together, our data highlights the pivotal role of SPRY4-IT1 in the tumorigenesis of HCC.