Bergapten (BP) is a plant-derived furocoumarin that has a wide range of pharmacological effects. BP serves as a candidate amplifier in phototherapy against skin inflammation, such as psoriasis and atopic dermatitis. However, the anti-inflammatory role of BP remains elusive. We utilized IL-17A-stimulated keratinocyte line and imiquimod-challenged BALB/c mice to imitate psoriasis-like inflammation. Inflammatory phenotypes were determined by expressions of inflammatory genes and cytokines, histopathological changes and activities of nuclear factor-κB (NF-κB) pathway. An RNA-seq analysis of rodent skin was performed to explore possible mechanism lying behind. SiRNAs and antagonist (TMS) against cytochrome P450 family 1 subfamily B member 1 (CYP1B1) were subsequently used to determine the role of CYP1B1 in psoriasis pathogenesis in vitro and in vivo. Overexpression of CYP1B1 with lentivirus further validate therapeutic effect of BP. BP significantly suppressed activation of the NF-κB pathway by inhibiting p65 phosphorylation and improved the inflammatory phenotype both in vitro and in vivo. We revealed the key role of CYP1B1 in regulating the activation of the NF-κB signaling pathway. Knock-down with siRNAs significantly reduce the expression of inflammatory genes and cytokines. An intraperitoneal injection of TMS partially remediated IMQ-induced inflammation, mainly in terms of skin thickness. Overexpression of Cyp1b1 led to increased expression of the CYP1B1 protein and rescued the therapeutic effect of BP in vitro. This study revealed that BP suppressed expression of Cyp1b1 in keratinocytes and inhibited the activation of NF-κB signaling pathway by blocking the phosphorylation of p65.