Adults with disabilities, a group including >25% of U.S. adults (1), experience higher levels of mental health and substance use conditions and lower treatment rates than do adults without disabilities* (2,3). Survey data collected during April-September 2020 revealed elevated adverse mental health symptoms among adults with disabilities (4) compared with the general adult population (5). Despite disproportionate risk for infection with SARS-CoV-2, the virus that causes COVID-19, and COVID-19-associated hospitalization and mortality among some adults with disabilities (6), information about mental health and substance use in this population during the pandemic is limited. To identify factors associated with adverse mental health symptoms and substance use among adults with disabilities, the COVID-19 Outbreak Public Evaluation (COPE) Initiative† administered nonprobability-based Internet surveys to 5,256 U.S. adults during February-March 2021 (response rate = 62.1%). Among 5,119 respondents who completed a two-item disability screener, nearly one third (1,648; 32.2%) screened as adults with disabilities. These adults more frequently experienced symptoms of anxiety or depression (56.6% versus 28.7%, respectively), new or increased substance use (38.8% versus 17.5%), and suicidal ideation (30.6% versus 8.3%) than did adults without disabilities. Among all adults who had received a diagnosis of mental health or substance use conditions, adults with disabilities more frequently (42.6% versus 35.3%; p <0.001) reported that the pandemic made it harder for them to access related care or medication. Enhanced mental health and substance use screening among adults with disabilities and improved access to medical services are critical during public health emergencies such as the COVID-19 pandemic.