Astilbin (AS) has been confirmed to be an attractive candidate drug for psoriasis; however, the low oral absorption limits its further development and utilization. Herein, a simple method was discovered to solve this problem, which was combined with citric acid (CA). The efficiency was estimated by imiquimod (IMQ)-induced psoriasis-like mice, and the absorption was predicted by the Ussing chamber model, HEK293-P-gp cells were used to validate the target. Compared with the AS group, the combination with CA significantly reduced the PASI score and down-regulated the protein expression of IL-6 and IL-22, which showed that the combination of CA enhanced the anti-psoriasis effect of AS. Moreover, AS concentration in psoriasis-like mice plasma was significantly increased (3.90-fold) in the CA combined group, and the mRNA and protein levels of P-gp in the small intestine of the combined group were decreased by 77.95 and 30.00%, respectively. In addition, when combined with CA, AS absorption significantly increased while the efflux ratio decreased in vitro. Furthermore, CA significantly elevated the uptake of AS by 153.37% and decreased the protein expression of P-gp by 31.70% in HEK293-P-gp cells. These results indicated that CA enhanced the therapeutic efficacy of AS by improving its absorption via down-regulation of P-gp.