ObjectiveIt is imperative that research identifies factors related to depression among individuals in substance use treatment, as depression is associated with substance use relapse. Dispositional mindfulness and spirituality may bear an important role in the relationship between depression and substance use. Method Using preexisting patient medical records (N = 105), the current study investigated dispositional mindfulness and spirituality in relation to depressive symptom clusters (affective, cognitive, and physiological) among men in residential substance use treatment. The mean age of the sample was 41.03 (standard deviation = 10.75). Results Findings demonstrated that dispositional mindfulness and spirituality were negatively associated with depressive symptoms. After controlling for age, alcohol use, and drug use, dispositional mindfulness remained negatively associated with all of the depression clusters. Spirituality only remained associated with the cognitive depression cluster. Conclusion Mindfulness‐based interventions may hold promise as an effective intervention for reducing substance use and concurrent depressive symptoms.