Female adolescents with disabilities are at an increased risk for mental health concerns, which can negatively impact their self-determination, making transition to postschool opportunities difficult. We analyzed two waves of survey data from 366 female adolescents with disabilities, recruited from 26 U.S. public high schools, as part of a randomized controlled trial of a career development intervention. Participants with mental health concerns evidenced a slower increase in self-determination over the follow-up period than those without such concerns. Individuals assigned to the intervention condition experienced significant gains in self-determination compared with the control. Findings suggest that mental health concerns can operate as a barrier to growth in self-determination skills among this population, though targeted interventions can help in boosting these skills.