Objective: In 2020, approximately 1.7 million people were incarcerated in the United States, with nearly half of the general population being related to, or romantically involved with, an incarcerated individual. Over 70% of these incarcerated individuals met the criteria for a co-occurring mental health and substance use diagnoses. Individuals with co-occurring disorders often experience high rates of recidivism, which negatively impacts their non-incarcerated partners. This study aimed to examine the impact of incarcerated individuals with co-occurring ADHD and depression on their relationship quality, focusing on the roles of substance use, substance use treatment, and self-efficacy. Methods: The study analyzed the effects of substance use, substance use treatment, and self-efficacy on the relationship quality of couples where one partner was incarcerated and diagnosed with co-occurring ADHD and depression. The direct and indirect influences of these factors on relationship quality were assessed. Results: The findings indicated that higher levels of substance use and depressive symptoms, along with lower levels of self-efficacy and substance use treatment, were associated with lower relationship quality. ADHD indirectly affected relationship quality via substance use (β = −.015, 95% CI [−0.023, −0.008]) and self-efficacy (β = −.027, 95% CI [−0.039, −0.016]). Depression had both direct effects on relationship quality (β = −.180, 95% CI [−0.224, −0.138]) and indirect effects via substance use (β = −.023, 95% CI [−0.033, −0.015]), self-efficacy (β = −.040, 95% CI [−0.056, −0.025]), and through substance use and substance treatment (β = −.002, 95% CI [0.001, 0.005]). Conclusion: These findings highlight the need for further research to explore combined substance use and mental health treatment programs. Such interventions could potentially reduce recidivism rates, and promote the quality and maintenance of relationships among incarcerated individuals and their partners.