After severe liver injury, biliary epithelial cells (BECs) undergo dedifferentiation into bipotential progenitor cells (BPPCs), which subsequently redifferentiate into nascent hepatocytes and BECs to accomplish liver regeneration. However, the critical factors governing the redifferentiation process of BPPCs remain largely unknown. Here, using a zebrafish model of severe liver injury, we observed specific expression of khdrbs1a and khdrbs1b (collectively known as khdrbs1) in BPPCs through single-cell RNA analyses and fluorescence in situ hybridization. Subsequently, to eliminate the genetic compensation, we generated a CRISPR/dead Cas9-mediated system for interfering khdrbs1 in BECs, which caused the defective liver regeneration and impaired redifferentiation of BPPCs. Furthermore, the khdrbs1-/- mutant displayed impaired proliferation and redifferentiation of BPPCs during liver regeneration. Mechanistically, p53 signaling was activated in response to the loss of khdrbs1, and tp53 mutation partially rescued the defective liver regeneration of the khdrbs1-/- mutant. In summary, we elucidate that Khdrbs1 promotes the redifferentiation of BPPCs in part by inhibiting p53 activation during biliary-mediated liver regeneration in zebrafish.