Objective To investigate the estrogen-like protective effect and mechanism of quercetin on free fatty acids (FFA)-induced hepatocyte steatosis. Methods Cell viability was detected by CCK-8 assay, and lipid accumulation in hepatocytes was observed by Oil Red O staining. Following administration of various estrogen intervention paradigms to HepG2 cells, the optimal drug intervention was determined to be post-treatment. HepG2 cells were exposed to different concentrations of estrogen and quercetin in a post-treatment manner to determine the optimal concentration of drug intervention. Cells were randomly divided into four groups: Control, model (FFA), positive drug estrogen control (E2), and quercetin (Que). Triglyceride (TG) levels were determined using the glycerol phosphate oxidase peroxidase (GPOPAP) method. Reactive oxygen species (ROS) levels were detected using DCFH-DA. Protein contents of tumor necrosis factor α ( TNF-α) were measured by enzyme-linked immunosorbent assay. Expression levels of peroxisome proliferatoractivated receptor γ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα),carnitine palmitoyl transferase 1α (CPT1α), and acetyl-CoA carboxylase ( ACOX1) were measured by Real-time PCR. Results It was determined that 1 μmol / L estrogen and 30 μmol / L quercetin post-treatment of HepG2 cells was optimal for subsequent experiments. Compared with the control group, numbers of red lipid droplets and TG contents were significantly increased (P<0. 001); expression levels of PGC-1α, PPARα, CPT1α and ACOX1 mRNA were significantly decreased (P<0. 05); ROS levels were increased; and TNF-α protein levels were significantly increased (P<0. 01) in the FFA group. Compared with the FFA group, both the estrogen and quercetin group displayed significantly reduced levels of red lipid droplets and ROS. Moreover, both the estrogen group (P<0. 05) and quercetin group (P<0. 05) exhibited significantly decreased TG contents, and both the estrogen group ( P< 0. 001) and quercetin group ( P< 0. 01) exhibited significantly upregulated expression of PGC-1α. In addition, both the estrogen group ( P< 0. 001) and quercetin group ( P< 0. 01) displayed significantly decreased TNF-α protein contents and significantly upregulated expression levels of PPARα ( P< 0.01),CPT1α (P<0. 001), and ACOX1 (P<0. 001). There was no significant difference in the above indicators between the quercetin group and estrogen group. Conclusions Quercetin exerts an estrogen-like effect by inducing expression of PGC-1α, activating fatty acid β oxidation, reducing oxidative stress, and inhibiting inflammatory response, ultimately improving hepatic steatosis.