IGF2BP1 overexpression promotes hepatocellular carcinoma (HCC) progression. Long non-coding RNA LIN28B-AS1 directly binds to IGF2BP1. In the present study, LIN28B-AS1 and IGF2BP1 expression and their potential functions in HCC cells were tested. Genetic strategies were applied to interfere their expression, and cell survival, proliferation and apoptosis were analyzed. We show that LIN28B-AS1 is expressed in established/primary human HCC cells and HCC tissues. RNA-immunoprecipitation (RIP) and RNA pull-down results confirmed that LIN28B-AS1 directly associated with IGF2BP1 protein in HCC cells. LIN28B-AS1 silencing (by targeted siRNAs) or knockout (KO, by CRISPR-Cas9 method) depleted IGF2BP1-dependent mRNAs (IGF2, Gli1, and Myc), inhibiting HCC cell growth, proliferation, migration, and invasion. Conversely, ectopic overexpression of LIN28B-AS1 upregulated IGF2BP1-dependent mRNAs and promoted HCC cell progression in vitro. Importantly, ectopic IGF2BP1 overexpression failed to rescue LIN28B-AS1-KO HepG2 cells. LIN28B-AS1 siRNA and overexpression were ineffective in IGF2BP1-KO HepG2 cells. In vivo, LIN28B-AS1 KO-HepG2 xenograft tumors grew significantly slower than the control tumors in the nude mice. Taken together, we conclude that LIN28B-AS1 associates with IGF2BP1 to promote human HCC cell progression in vitro and in vivo.