A study was conducted to determine the effects of zearalenone (ZEN) on the mRNA expression of pregnane X receptor (PXR), constitutive and rostane receptor (CAR), and phase I and II enzymes as well as the toxicity in the liver of female weanling piglets. Thirty-two female weanling piglets (Duroc × Landrace × Large white, 12.27 ± 0.30 kg)were divided into four groups (n = 8 piglets/group) that were supplemented with 0 (control), 0.5, 1 or 2 mg/kg ZEN. The trial period lasted for 28 d. The results showed that the ZEN supplementation in the diets (0.5–2 mg/kg) had no effect on growth performance but dose-dependently increased serum aspartate aminotransferase, alanineaminotransferase, alkaline phosphatase, and γ-glutamyltransferase activities (P < 0.05). The ZEN residue in the liver (P < 0.01) was also linearly and dose-dependently increased. Furthermore, the mRNA expression of PXR, CAR, phase I enzymes (i.e., cyp2e1, cyp3a5, cyp2a6, cyp1a1, and cyp1a2), and phase II enzymes (i.e., gsta1, gsta2, ugt1a3) significantly increased linearly in a dose-dependent manner (P < 0.05). However, the spleen relative weight and the glutathione peroxidase activity in the liver (P < 0.05) linearly decreased as the dietary ZEN concentration increased; the mRNA expression of the nuclear receptors PXR and CAR is responsive to ZEN in female piglets, and ZEN increases the mRNA expression of their target genes. This finding shows that the nuclear receptor signaling system plays an important role in the defense against ZEN.