Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR^−/− mice, but not in hypothyroid PXR^−/− mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR^−/− hypothyroid mice, and this induction was abolished in CAR^−/− mice and in and CAR^−/− PXR^−/− double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR^−/− mice and lowest in WT and PXR^−/− mice. Hypothyroid WT or PXR^−/− mice survived chronic CBZ treatment, but all hypothyroid CAR^−/− and CAR^−/− PXR^−/− mice died, with CAR^−/−PXR^−/− mice surviving longer than CAR^−/− mice (12.3±3.3days vs. 6.3±2.1days, p=0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge.