The loss of loricrin, a major component of the cornified envelope, results in a delay of epidermal barrier formation. Therefore, the living layers of the epidermis are aberrantly exposed to late-stage amniotic fluid, which may serve as the signal to upregulate genes that functionally compensate for the loss of loricrin. Consistent with this hypothesis, metabolomic studies revealed marked changes in amniotic fluid between E14.5 and E16.5 days postcoitum. In addition, we discovered that the Nrf2/Keap1 pathway detects these compositional changes and directly upregulates the expression of genes involved in the compensatory response, thus ensuring postnatal survival. In support of this finding, we demonstrate that genetically blocking the Nrf2 pathway abolishes the compensatory response and that preemptively activating Nrf2 pharmacologically rescues the delay in barrier formation in utero. Our findings reveal that the functions of Nrf2 and the composition of amniotic fluid have coevolved to ensure the formation of a functional barrier. ► Nrf2-activating metabolites are present in late-stage amniotic fluid ► Sprr2d and Sprr2h are direct downstream targets of Nrf2 in the epidermis ► Blocking the Nrf2 pathway in the loricrin null mouse results in postnatal lethality ► Pharmacological activation of Nrf2 in utero rescues the delay in barrier formation Mutations in epidermal differentiation genes often cause a developmental delay in epidermal barrier formation, which must be resolved before birth to ensure survival. Huebner et al. discover that aberrant in utero exposure of keratinocytes to late-stage amniotic fluid activates the Nrf2/Keap1 pathway, and this compensatory mechanism rescues barrier formation.