Objective To explore the mechanism by which long non-coding RNA SNHG16 (lncRNA SNHG16) promotes liver cancer cell resistance to sorafenib by regulating microRNA-570 (miR-570). Methods Real-time fluorescent RT-PCR was used to detect lncRNA SNHG16 and miR-570 expression of human normal liver tissue and liver cancer cells, HepG2 and HepG2-R. HepG2-R cells were transfected to provide the following groups: HepG2-R+pcDNA, HepG2-R+ pcDNA SNHG16, HepG2-R+anti-miR-NC, HepG2-R+anti-miR-570, and HepG2-R+pcDNA group. HepG2-R+SNHG16+ miR-NC and HepG2-R+pcDNA SNHG16+miR-570 groups were used for follow-up tests. miR-NC, miR-570, si-NC, and si-SNHG16 were transfected into HepG2 cells in the same way to give HepG2+miRNC, HepG2+miR-570, HepG2+si-NC, and HepG2+si-SNHG16 groups. MTT assay, flow cytometry and Transwell assay were used to detect cell proliferation, apoptosis, and invasion. Western blot assay was used to detect the changes in expression of CyclinD1, P21, MMP-9, and MMP-2. Results Compared with normal liver tissue, the liver cancer tissue showed increased lncRNA SNHG16 and decreased miR-570 expression (P< 0. 05). Compared with the normal cell HepG2-P group, the HepG2-R group had increased lncRNA SNHG16 and IC₅₀ values, and the inhibition rates of miR-570 in HepG2-R cells were decreased at sorafenib concentrations of 1, 2, 4, 8, 16 μmol/ L (P<0. 05). In the HepG2-R+pcDNA SNHG16 overexpression group, lncRNA SNHG16 expression was significantly increased (P<0. 05). Compared with the HepG2-R+pcDNA group, the HepG2-R+pcDNA SNHG16 group’s number of migrated cells and expression of CyclinD1, P21, MMP-9, and MMP-2 were decreased, while the inhibition rate, apoptosis rate, and P21 expression were increased (P<0. 05). Compared with the HepG2-R+anti-miR-NC group, the HepG2-R+anti-miR-570 group’ s miR-570 levels were decreased (P< 0. 05). Compared with the HepG2-R + anti-miR-NC group, the HepG2-R + anti-miR-570 group showed decreased levels of CyclinD1, MMP-9, and MMP-2 and increased inhibition rate, apoptosis rate, and P21 expression (P<0. 05). A dual luciferase reporting experiment showed that, compared with the miR-NC group, miR-570 reduced WT-SNHG16 luciferase activity (P<0. 05), but there was little effect on the luciferase activity of MT-SNHG16 (P>0. 05). Overexpression of lncRNA SNHG16 decreased the expression of miR-570 in HepG2-R cells (P< 0. 05). Compared with the HepG2-R+ pcDNA SNHG16+ miR-NC group, the HepG2-R + pcDNA SNHG16 + miR-570 group’ s number of migrated cells and expression levels of CyclinD1, MMP-9, and MMP-2 were increased, while the inhibition rate, apoptosis rate, and P21 expression were decreased (P<0. 05). Conclusions lncRNA SNHG16 can regulate the drug resistance of HepG2-R liver cancer cells. The mechanism is related to the targeted regulation of miR-570 by lncRNA SNHG16, thus miR-570 provides a new target for the clinical treatment of liver cancer cells.