Youth experiencing homelessness experience violence victimization, substance use, suicide risk, and sexual risk disproportionately, compared with their stably housed peers. Yet few large-scale assessments of these differences among high school students exist. The youth risk behavior survey (YRBS) is conducted biennially among local, state, and nationally representative samples of U.S. high school students in grades 9–12. In 2019, 23 states and 11 local school districts included a measure for housing status on their YRBS questionnaire. The prevalence of homelessness was assessed among states and local sites, and relationships between housing status and violence victimization, substance use, suicide risk, and sexual risk behaviors were evaluated using logistic regression. Compared with stably housed students, students experiencing homelessness were twice as likely to report misuse of prescription pain medicine, three times as likely to be threatened or injured with a weapon at school, and three times as likely to report attempting suicide. These findings indicate a need for intervention efforts to increase support, resources, and services for homeless youth.