Background/Objectives: The present systematic review analyses the neuroradiological findings in subjects with axis I psychiatric disorders (i.e., bipolar, major depressive, schizophrenic, anxiety, and post-traumatic stress disorders) and comorbid substance use disorder in order to elucidate the organic changes that occur in the brains of people suffering from both conditions. Methods: We analysed and compared the different neuroimaging findings extracted from 93 studies and 10,823 patients; articles were obtained from three databases (Scopus, PubMed [Medline], and the Cochrane Controlled Register of Trials [Central]) and subjected to specific eligibility criteria. We selected articles that assessed patients with axis I psychiatric conditions and a comorbid substance abuse disorder; articles had to report relevant neuroimaging findings and bias was assessed via the Newcastle–Ottawa scale. Results: Significant findings were found on the structure or function of psychiatric patients’ brains with comorbid substance abuse, with certain key areas that were further affected by substance use, especially in areas involved in reward processing, with reductions in volume and connectivity and the augmentation of stimuli-related activity. Conclusions: These results present important implications on the current understanding of psychiatric disorders and comorbid substance use, on the importance of neuroradiological tools in the diagnosis and treatment of these disorders, and on the search for potential new targets for the treatment of psychiatric disease and substance addiction.