Opioid use disorder (OUD) continues to be a significant problem in the United States, contributing to overdose and death. Recent efforts to expand access to treatment of OUD in primary care have increased the availability of medications for OUD (MOUDs). However, OUD is often accompanied by poor mental health and well-being, and it is not known if treatment with MOUDs alone is associated with improved psychological well-being. This study's purpose was to examine changes in mental health and well-being in the first 6 months of treatment with MOUDs in a family medicine residency clinic. Patients (N = 126; M age = 34.6 years, SD = 10.6; 54.8% male; 71.4% white) completed validated screeners of mental health and well-being (depression, anxiety, anger, loneliness, perceived stress, meaning in life, and life satisfaction) at baseline (induction visit for buprenorphine), 1-month, and 6-months. Results indicated that the mental health and well-being indices did not significantly change over the first 6 months of treatment on MOUDs. There were initial decreases in depression and anxiety at 1-month; however, both increased and were equivalent to baseline levels at 6-months. These results suggest that MOUD treatment alone does not significantly impact mental health or well-being in patients with OUD. Additional treatments or supports are clearly needed to address the comorbid mental health and well-being challenges in this population, as these factors can be both antecedents and consequences of substance misuse.