In the present study, we demonstrated for the first time that (1) G. cambogia suppressed hepatic steatosis and apoptosis in the liver of HFD-fed mice and in FFA-treated HepG2 cells; (2) G. cambogia inhibited HFD- and FFA-induced upregulation of C/EBPα and PPARγ expression, and FASN, FABP4, and SCD transcription to regulate lipogenesis; (3) G. cambogia reduced the HFD- and FFA-induced alterations of the Bcl-2/BAX ratio and PARP cleavage to regulate apoptosis; and (4) these normalizations were due to the antioxidant effect of G. cambogia and HCA through NRF2-ARE pathway activation. This evidence concerns the gene SCD and fatty liver disease.