As a member of alpha-coronaviruses, PEDV could lead to severe diarrhea and dehydration in newborn piglets. Given that lipid peroxides in the liver are key mediators of cell proliferation and death, the role and regulation of endogenous lipid peroxide metabolism in response to coronavirus infection need to be illuminated. The enzymatic activities of SOD, CAT, mitochondrial complex-I, complex-III, and complex-V, along with the glutathione and ATP contents, were significantly decreased in the liver of PEDV piglets. In contrast, the lipid peroxidation biomarkers, malondialdehyde, and ROS were markedly elevated. Moreover, we found that the peroxisome metabolism was inhibited by the PEDV infection using transcriptome analysis. These down-regulated anti-oxidative genes, includingGPX4,CAT,SOD1,SOD2,GCLC, andSLC7A11, were further validated by qRT-PCR and immunoblotting. Because the nuclear receptor RORγ-driven MVA pathway is critical for LPO, we provided new evidence that RORγ also controlled the genesCATandGPX4involved in peroxisome metabolism in the PEDV piglets. We found that RORγ directly binds to these two genes using ChIP-seq and ChIP-qPCR analysis, where PEDV strongly repressed the binding enrichments. The occupancies of histone active marks such as H3K9/27ac and H3K4me1/2, together with active co-factor p300 and polymerase II at the locus ofCATandGPX4, were significantly decreased. Importantly, PEDV infection disrupted the physical association between RORγ and NRF2, facilitating the down-regulation of theCATandGPX4genes at the transcriptional levels. RORγ is a potential factor in modulating theCATandGPX4gene expressions in the liver of PEDV piglets by interacting with NRF2 and histone modifications.