Background Prurigo nodularis (PN) is a chronic inflammatory, pruritic skin disorder characterized by raised papules and hyperkeratotic nodules. PN has been linked to malignancy, though cancer types and mechanisms remain unclear. To analyze the relationship between PN and skin cancer, we used the All of Us Research Program, a U.S.-based electronic health record and genomic database with data from over one million participants, to assess PN and cutaneous neoplasms. Methods We identified 869 individuals with PN using concept ID 4272156 and propensity matched them to two controls (n = 1738) based on age, sex, race, and ethnicity. Diagnoses of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma were identified through curated concept sets and relevant concept IDs to maximize capture. We extracted demographic and clinical variables, smoking status, insurance, income, family skin cancer history, and healthcare use. Univariate associations were tested using χ2 or Fisher’s exact t-test. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Multivariable logistic regression models were adjusted for age, race, ethnicity, sex, income, insurance, smoking status, family history of skin cancer, and healthcare utilization. Results PN cases had a higher prevalence of any NMSC (16.3% vs 5.2%; P < 0.001), with significant increases in BCC (11.4% vs 3.9%; P < 0.001), SCC (9.7% vs 1.8%; P < 0.001) and melanoma (4.3% vs 1.5%; P < 0.001). Univariable logistic regression showed PN was associated with increased odds of BCC (OR 3.16; 95% CI 2.29–4.35; P < 0.001), SCC (OR 5.89; 95% CI 3.87– 8.97; P < 0.001) and melanoma (OR 2.93; 95% CI 1.76–4.87; P < 0.001). These associations persisted after multivariable adjustment for demographics, risk factors, and healthcare utilization, with adjusted OR (aOR) 3.31 (95% CI 2.33–4.69; P < 0.001) for BCC, aOR 6.09 (95% CI 3.89– 9.53; P < 0.001) for SCC and aOR 3.01 (95% CI 1.77–5.13; P < 0.001) for melanoma. Conclusion Chronic scratching and repeated trauma to the skin, hallmarks of PN, may lead to inflammation and compromised skin barrier integrity, potentially promoting keratinocyte carcinogenesis. PN is associated with a chronic Th2-skewed inflammatory milieu—characterized by elevated IL-4 and IL-13, and prolonged use of immunosuppressants may similarly impair antitumor immunity. Future PN studies should examine IL-4/IL-13 pathway inhibitors on long-term cancer risk. Given the potential association with cutaneous neoplasms, routine skin exams may be appropriate in individuals with long-standing or extensive PN.