Both depression and substance use disorders represent major global public health concerns and are often co-occurring. Although there are ongoing discoveries regarding the pathophysiology and treatment of each condition, common mechanisms and effective treatments for co-occurring depression and substance abuse remain elusive. Mindfulness training has been shown recently to benefit both depression and substance use disorders, suggesting that this approach may target common behavioral and neurobiological processes. However, it remains unclear whether these pathways constitute specific shared neurobiological mechanisms or more extensive components universal to the broader human experience of psychological distress or suffering. We offer a theoretical, clinical and neurobiological perspective of the overlaps between these disorders, highlight common neural pathways that play a role in depression and substance use disorders and discuss how these commonalities may frame our conceptualization and treatment of co-occurring disorders. Finally, we discuss how advances in our understanding of potential mechanisms of mindfulness training may offer not only unique effects on depression and substance use, but also offer promise for treatment of co-occurring disorders.