Early growth response (Egr) factors are involved in tissue development and repair. However, few studies have focused on the role of egr genes in renal regeneration after acute kidney injury (AKI) and the underlying mechanisms. In this study, we observed that egr1 and egr4 were sharply upregulated in wild type zebrafish at 1 day post-injury by gentamicin. Further experiments with egr1 and egr4 mutants showed that egr1 and egr4 were involved in zebrafish renal regeneration after AKI by regulating the proliferation and apoptosis of tubular cells. foxm1 is expressed in injured kidneys and involved in kidney repair. Loss of foxm1 inhibited zebrafish renal regeneration by decreasing the proliferation and increasing the apoptosis of tubular cells. Moreover, Egr1 and Egr4 promoted foxm1 expression by directly binding to the foxm1 promoter, thus regulating renal regeneration. Our results revealed that the rapid and transient induction of egr1 and egr4 after AKI exerts a renoprotective role through upregulating foxm1 to facilitate kidney regeneration. Therefore, the egr1/egr4–foxm1 regulatory axis holds a therapeutic potential for the treatment of AKI.