We examine whether perceived interpersonal discrimination mediates the association between disability and psychological well-being (depression, negative and positive affect) and how these processes differ across the life course. Data are from two waves (2004–2006; 2013–2014) of the Midlife in the United States (MIDUS; N = 2,503). Perceived discrimination accounts for 5% to 8% of the association between disability and the three mental health outcomes. Moderated mediation analyses reveal significant age differences; perceived discrimination is a stronger explanatory mechanism among midlife (ages 40–64) relative to older (age 65+) adults. Disability stigma takes a heightened psychological toll at midlife, a life stage when adults are expected to be able-bodied and interact with a diverse social network, which may be a source of interpersonal mistreatment. Among older adults, for whom impairment is expected and common, the psychological impact of disability may operate through other pathways. We discuss implications for research and practice.