Background: People with disabilities (PwDs) experience challenges that limit their social participation and violate their rights, contradicting those established in the Convention on the Rights of Persons with Disabilities. Objective: This study investigated the quality of life and social participation of PwDs in 10 municipalities in the department of Antioquia, Colombia. Methods: It used a mixed approach that combined quantitative and qualitative methods. Participants included 464 PwDs for quantitative analysis and 246 territorial stakeholders for qualitative analysis. A collection instrument was validated based on the judgment of experts and the content validity coefficient. Results: The findings revealed that most PwDs lived in households belonging to low socioeconomic strata. In addition, obstacles to accessing education, employment, and assistive technology as well as restrictions on social participation were identified. Conclusions: These results suggest that the quality of life and social participation of PwDs in various aspects are compromised.