Objective To establish a HepG2 cell line with downregulated heterogeneous nuclear ribonucleoprotein K (HNRNPK) mediated by lentivirus and study the effects of HNRNPK downregulation on cell proliferation and migration. Methods HepG2 cells were infected with packaged lentivirus, and positive cells were selected to obtain stable transgenic cell lines. Then detected expression efficiency of HNRNPK. The effect of HNRNPK downregulation on cell proliferation was detected using cell counting CCK-8 and colony formation assays. The effect of HNRNPK downregulation on cell migration was detected using the wound healing and Transwell assays. Results The HepG2 cell line with downregulated HNRNPK mediated by lentivirus infection was successfully constructed. HNRNPK-downregulation inhibited the proliferation and migration of HepG2 liver cells. Conclusions HNRNPK-downregulation inhibits the proliferation and migration of HepG2 liver cells in vitro.