Background: The link between attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) has been largely demonstrated. Some scholars have hypothesized that self-regulation mechanisms might play a key role in explaining this association. Objective(s): The current study tested the hypothesis that retrospective childhood ADHD symptoms might lead to more severe SUDs and this association should be mediated by current self-ratings of behavioral disinhibition, inattention, and emotional dysregulation among 204 treatment-seeking adults (male: 67.3%; female: 32.7%) with a primary diagnosis of alcohol use disorder and other SUDs. Methods: The mediational model was estimated through self-report measures of childhood ADHD symptoms (independent variable; WURS), current self-regulation mechanisms (mediators)—behavioral disinhibition (BIS-11 motor subscale), difficulties with attention regulation (MAAS) and emotion regulation (DERS)—and severity of SUDs (dependent variable; SPQ alcohol, illicit and prescribed drugs). Results: The analysis showed that alterations in the self-regulation system fully mediated the association between the severity of childhood ADHD symptoms and SUDs in adulthood. Behavioral disinhibition and difficulties in attention regulation were the most representative alterations in self-regulation processes that explained this association. Conclusions: These findings suggest it is useful to implement several therapeutic approaches (e.g. behavioral, mindfulness-based, and pharmacological) to increase the self-regulation abilities of children and adolescents with ADHD in order to reduce the probability of SUD onset in adulthood. However, future longitudinal neuroimaging and neuropsychological studies are needed to further support the role of self-regulation mechanisms in explaining the prospective association between childhood ADHD symptoms and SUDs in adulthood.