ZNFX1 Antisense RNA 1 (ZFAS1) act as an oncogenic long noncoding RNA in multiple types of cancer. Ferroptosis is an iron-dependent cell death characterized by excessive iron accumulation and lipid peroxidation. However, to date, the functional role and mechanism of ZFAS1 in ferroptosis in hepatocellular carcinoma (HCC) remains largely unknown. The present study revealed that ZFAS1 was upregulated in HCC and upregulation of ZFAS1 indicated poor clinical outcome of HCC patients. Loss- and gain-of-function experiments demonstrated that knockdown of ZFAS1 inhibited HCC cell proliferation and induced ferroptosis, while overexpression of ZFAS1 exerted opposite effects. ZFAS1 enhanced cell proliferation via suppression of ferroptotic death. Mechanistically, ZFAS1 interacted with miR-150 and decreased its expression. AIFM2, the critical ferroptosis protector, was a direct target of ZFAS1/miR-150. ZFAS1 accelerated HCC proliferation and inhibited ferroptosis by the regulation of the miR-150/AIFM2 axis. These discoveries intimate an essential part of ZFAS1/miR-150/AIFM2 in governing HCC ferroptosis, which may provide a promising therapeutic strategy for HCC patients.