Chronic subdural hematoma (CSDH) is one of the most common neurological disorders. In recent years, atorvastatin (ATV) combined with dexamethasone (DXM) has been proved to be a more efficacious therapy in treating patients with CSDH than ATV monotherapy. Our recent study found that ATV in hematoma fluid was higher in patients receiving ATV combined with DXM, as compared to those receiving ATV monotherapy. However, the underlying mechanism of how DXM improves the level of ATV is not yet clear. The purpose of this study was to investigate the effects of DXM on pharmacokinetics of ATV and the expression of organic anion transport polypeptides 1B1 (OATP1B1) and upstream nuclear receptors liver X receptor α (LXRα) in rat liver and HepG2 cells were evaluated. The results showed that when DXM was combined with ATV, the area under curve (AUC_(0~∞)) of ATV, o- ATV andp- ATV was increased by 1.550, 1.420, 1.676 times, respectively. In HepG2 cells, DXM inhibited the uptake of ATV by 59.24%. Also, DXM decreased the expression of OATP1B1 and LXRα both in the rat liver and HepG2 cells. Dual-luciferase reporter assay indicated that DXM had an inhibitory effect on the LXRα-OATP1B1 pathway. In conclusion, DXM downregulated the protein expression of OATP1B1 by inhibiting the LXRα-OATP1B1 pathway, thus, decreasing hepatic drug uptake and increasing plasma concentration of ATV and its active metabolites.