Few research studies evaluating the impact of dermatologic diseases in the United States (US) have adequately included underrepresented groups. All of Us (AoU) is an ongoing precision medicine-based research initiative by the National Institutes of Health (NIH) that facilitates research in populations traditionally underrepresented in biomedical research by prioritizing them for data collection. Our objective was to evaluate the burden of onychomycosis in underrepresented groups defined by the framework provided by AoU. The AoU Registered Tier dataset version 5 was used which includes data collected between May 30, 2017 and April 1, 2021. We conducted a cross-sectional analysis linking survey and electronic health record (EHR) data to estimate the prevalence of onychomycosis in underrepresented groups defined by race, ethnicity, age (≥75 years), disability, sexual orientation/gender identity (LGBTQIA+), income (annual household income ≤$35 000) and education (less than a high school degree). The latest All of Us data release includes 329,038 participants. Of these, 251,597 (76%) had EHR data and 13,874 had onychomycosis (overall prevalence, 5.5%; 95% CI, 5.4– 5.6). Multivariate analyses adjusted by tinea pedis, diabetes mellitus, immune compromise, nail psoriasis, and insurance status, in addition to the aforementioned variables, revealed that, compared with White participants, Black and Hispanic participants had a higher adjusted odds of onychomycosis (OR, 1.29; 95% CI, 1.23–1.36 and OR, 1.24; 95% CI, 1.17–1.31, respectively). Higher adjusted odds of onychomycosis were also observed in underrepresented groups. Our findings suggest a disproportionately high burden of onychomycosis in underrepresented groups, although further studies are needed to replicate our findings and address this disparity.