BACKGROUND: Patients with chronic pain, depression, and substance use disorder (SUD) are often treated in primary care settings. An estimated 52% of patients have a diagnosis of chronic pain, 5% to 13% have depression, and 19% have SUD. These estimates are likely low when considering the fact that 50% of primary care patients with depression and 65% with SUD are undiagnosed or do not seek help. These three conditions have overlapping neurophysiological processes, which complicate the treatment outcomes of a primary physical illness. Behavioral interventions have been widely utilized as adjunctive treatments, yet little is known about what types of behavioral interventions were effective to treat these comorbidities. This systematic review aimed to identify behavioral interventions targeting chronic pain, depression, and SUD in primary care settings. METHODS: The Cumulative Index to Nursing and Allied Health Literature, Medline, PsycInfo, and Google Scholar databases were searched to identify randomized controlled trials, using a behavioral intervention, involving adults with at least two of the three conditions. RESULTS: This search yielded 1,862 relevant records, and six articles met final selection criteria. A total of 696 participants were studied. Behavioral interventions varied in content, format, and duration. Mindfulness Oriented Recovery Enhancement (MORE), Acceptance and Commitment Therapy (ACT), Interpersonal Psychotherapy adapted for pain (IPT-P), and Cognitive Behavioral Therapy (CBT) showed promising improvements across all studies, albeit with small to moderate effects. CONCLUSIONS: MORE, ACT, and CBT combined with mindfulness and Motivational Interviewing had the most promising results for treating chronic pain, depression, and SUD in various combinations in primary care settings. CLINICAL RELEVANCE: The evidence is mounting that behavioral interventions such as mindfulness-based or cognitive-behavioral interventions are effective strategies for managing patients with comorbidities of chronic pain, depression, and SUD in primary care. Integrated delivery of behavioral interventions via group sessions, computers, and smart phones may increase patient access to treatment; save time and cost; reduce stigma, patient distress, family burden, and healthcare fragmentation; and provide a ray of hope to amplify conventional treatments.