Background: Microaggression toward marginalized groups, including disabled persons, has received increasing attention in the literature. Little is known, however, as to factors that mitigate against their impact. Objective: The purpose of this study was to conduct a mediation analysis to infer the role of ableist microaggressions between self-esteem and perceived stress. Methods: Survey data from 254 self-identified persons with disabilities completed measures assessing self-esteem, stress, and ableist microaggressions. Findings: There was a negative association that was partially mediated by ableist microaggressions. Thus, persons with lower self-esteem experienced greater levels of stress due to the negative impact of ableist microaggressions. Conclusions: These findings corroborate results from other studies that people with disabilities are clearly impacted by ableist microaggressions, which contribute to their stress levels. Rehabilitation counselors and other health professionals should pay attention to the impact of ableist microaggressions on the well-being of clients with disabilities. Also, helping professionals should have greater awareness as to how they may inadvertently contribute to such microaggressions as part of professional practice. In terms of clinical practice, intervention strategies should be developed to improve self-esteem and coping with the impact of ableism. Findings indicate lower self-esteem is mediated by ableist microaggressions. Persons with disabilities who seek counseling services as a way to improve self-esteem may benefit from teaching them strategies on how to recognize ableist microaggressions and how to effectively address them when they occur.