Drug overdose deaths remain a public health crisis in the United States; nearly 107,000 and nearly 108,000 deaths occurred in 2021 and 2022, respectively. Persons with mental health conditions are at increased risk for overdose. In addition, substance use disorders and non-substance-related mental health disorders (MHDs) frequently co-occur. Using data from CDC's State Unintentional Drug Overdose Reporting System, this report describes characteristics of persons in 43 states and the District of Columbia who died of unintentional or undetermined intent drug overdose and had any MHD. In 2022, 21.9% of persons who died of drug overdose had a reported MHD. Using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria, the most frequently reported MHDs were depressive (12.9%), anxiety (9.4%), and bipolar (5.9%) disorders. Overall, approximately 80% of overdose deaths involved opioids, primarily illegally manufactured fentanyls. Higher proportions of deaths among decedents with an MHD involved antidepressants (9.7%) and benzodiazepines (15.3%) compared with those without an MHD (3.3% and 8.5%, respectively). Nearly one quarter of decedents with an MHD had at least one recent potential opportunity for intervention (e.g., approximately one in 10 decedents were undergoing substance use disorder treatment, and one in 10 visited an emergency department or urgent care facility within 1 month of death). Expanding efforts to identify and address co-occurring mental health and substance use disorders (e.g., integrated screening and treatment) and strengthen treatment retention and harm reduction services could save lives.