Limited studies have evaluated the effectiveness of vortioxetine in real-world settings, and none of them has involved patients with dual depression (major depressive disorder MDD and substance use disorder SUD). The objective of the study was to describe the effectiveness of vortioxetine in clinical practice and determine its effect on affective symptoms, cognitive function, quality of life, and substance use in patients with MDD and SUD. Post-authorization, retrospective, multicenter, descriptive, and observational study in 80 patients with MDD and SUD receiving a maintenance treatment with vortioxetine for six months between January 2017 and April 2021. Compared with baseline, scores significantly decreased after 3 and 6 months of treatment in the Montgomery-Åsberg Depression Rating Scale total (from 28.9 to 17.7 and 12.0), and global functional impairment of the Sheehan Disability Inventory (from 26.3 to 19.1 and 16.7). The number of correct answers in the symbol digit modalities test significantly improved during vortioxetine treatment (from 40.4 to 43.8 and 48.4). Regarding the clinical global impression scale, the score for disease severity significantly decreased from 3.8 to 3.0 and 2.4. Compared with baseline, there was a significant reduction in consumption of practically all substances, especially of alcohol, cannabis, and cocaine. Vortioxetine was effective in clinical practice for alleviating depressive symptoms and functional impairment, and in improving cognitive and executive functions and disease severity in patients with MDD and SUD. Moreover, the treatment with vortioxetine favored a reduction in substance use and the severity of the SUDs.