Prurigo nodularis (PN) is a chronic inflammatory skin disease that disproportionately affects African Americans and is characterized by pruritic skin nodules of unknown etiology. Little is known about genetic alterations in PN pathogenesis, especially relating to somatic events which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 PN patients and 10 atopic dermatitis (AD) patients for comparison. Somatic mutational analysis revealed that PN lesional skin harbors pervasive somatic mutations in fibrotic, neurotropic, and cancer-associated genes. Nonsynonymous mutations were most frequent in NOTCH1 and the Notch signaling pathway, a regulator of cellular proliferation and tissue fibrosis, and NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, showed that recurrently deleted and downregulated genes in PN lesional skin are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, multi-center data revealed a significantly increased risk of NOTCH1-associated diseases in PN patients. In characterizing the somatic landscape of PN, we uncover novel insights into its pathophysiology and identify a role for dysregulated Notch signaling in PN.