Background: The COVID-19 pandemic might negatively impact the quality of life and functional autonomy of Spanish adults with intellectual disability, and meaningful activities could prevent this negative progression. Methods: This is a prospective cohort study in Spanish adults with intellectual disability during the COVID-19 pandemic. Quality of life, functional autonomy and functional independence were measured. The meaningful activities studied were structured-leisure, community self-management, and occupational and physical activities. Results: Seventy-three participants were included in the study. Quality of life and functional autonomy significantly deteriorated during the COVID-19 pandemic (all p > 0.001). Greater participation in community self-management activities before COVID-19 was associated with less detriment to quality of life ([beta] = -0.312; p = 0.008), while greater participation in occupational and physical activities was associated with less detriment to the performance of instrumental activities ([beta] = -0.317; p = 0.016; and [beta] = -0.285; p = 0.030, respectively). Conclusion: People with intellectual disability living in residential homes experienced a decrease in their quality of life and functional autonomy during the COVID-19 pandemic. Their involvement in community self-management activities and physical and occupational activities before the pandemic had preventive effects on the detriment to the quality of life and functional autonomy.