This study tested a sequential mediation model that emotion-oriented coping and motivation for change mediate the relations between anxiety and depressive symptoms and the change in substance use. Data included 183 substance using women, randomly assigned to family therapy (N = 123) or individual therapy (N = 60). They reported their baseline anxiety and depressive symptoms, emotion-oriented coping, as well as motivation for change throughout treatment, and substance use over a time period of 1.5 years. Latent growth curve modeling showed that increased baseline motivation was associated with a faster decline in alcohol and drug use. Moreover, higher baseline anxiety and depressive symptoms were associated with a faster decrease in drug use through higher emotion-oriented coping and higher baseline motivation. This study underscores the importance of emotion-oriented coping in increasing clients' motivation and reducing their drug use.