The ubiquitin ligase Nedd4-1 plays key roles in organ development, tissue homeostasis and cancer, but its functions in the skin are largely unknown. Here we show perturbations in keratinocyte proliferation and terminal differentiation, epidermal barrier function, and hair follicle cycling as well as increased UV-induced apoptosis in mice lacking Nedd4-1 in keratinocytes. In particular, re-epithelialization of full-thickness excisional wounds was delayed in the mutant mice. This was caused by severely impaired migration and proliferation of Nedd4-1-deficient keratinocytes. Therefore, a few keratinocytes, which had escaped recombination and expressed Nedd4-1, obtained a growth advantage and contributed to re-epithelialization. Mechanistically, Nedd4-1-deficient keratinocytes failed to efficiently activate the Erk1/2 mitogen-activated kinases and the YAP transcriptional co-activator. These results identify Nedd4-1 as an essential player in wound repair through its effect on mitogenic and motogenic signaling pathways in keratinocytes.