We found that C1QTNF1-AS1 could inhibit proliferation, migration, invasion and JAK/STAT signaling pathway and promote apoptosis in HCC cells by suppressing miR-221-3p and fatherly promoting SOCS3. The novel C1QTNF1-AS1/miR-221-3p/SOCS3 regulatory axis was elucidated in HCC tissues and cells. The gene discussed is C1QTNF1; the disease is hepatocellular carcinoma.