Smoking is the leading preventable cause of death and disease in the world and represents a critical public health problem. Smokers with substance use disorders and depressive symptoms have particular difficulties quitting smoking and represent an underserved population. The current study utilized a novel behavioral activation (BA)−enhanced smoking cessation treatment with three clients in residential substance use treatment who had elevated depressive symptoms. We present detailed descriptions of the treatment they received and the challenges they faced. Our clients, who received five individual BA-enhanced smoking cessation sessions and two follow-up booster sessions, benefited significantly from the BA treatment. Over an 8-week follow-up period, they did not relapse to smoking and experienced significant decreases in depressive symptoms. This suggests BA may be a beneficial treatment strategy for this particularly challenging population.