Hypotrachyna oprah is described as new to science from collections made at locations in southeastern North America (Alabama, Florida, North Carolina). The species is considered rare and was potentially confused with H. osseoalba in the past. It differs from H. osseoalba in having capitate soralia and producing echinocarpic acid, together with related substances, in the medulla. The specific epithet was chosen to honor Dr. Oprah Winfrey for her performances, media presence, and generous philanthropy that have substantially improved humanity.