Adolescence is a phase characterized by reckless and risky behaviors, including the initiation and use of various illicit substances such as cannabis and alcohol. When ingested or administered, these substances affect mental processes by delivering pleasure, inner peace, and satisfaction. The aim of this study was to determine the prevalence and associated factors of psychoactive substance (PAS) use among adolescents. A cross-sectional study was conducted, including 300 participants surveyed using a structured questionnaire. Data were collected using the Mediterranean School Survey Project on Alcohol and Other Drugs (MedSPAD) to assess substance use, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to diagnose substance use disorders (SUDs), and the Early Trauma Inventory Self-Report Short Form (ETISR-SF) to identify childhood maltreatment, as well as socio-demographic characteristics. During the study period, 300 secondary school students participated. Their mean age was 17.92 ± 1.40 years, ranging from 15 to 22. There were slightly more males (56.7%) than females. A total of 40.67% of participants admitted to using at least one PAS at least once, while the prevalence of current use was 26%. Tobacco was the most commonly used substance (22.1%), followed by cannabis (7.33%). According to the DSM-5, 40.2% of users met the criteria for severe addiction. Factors associated with PAS use included the father’s level of education; place of use (e.g., home); poor relationships with parents, siblings, and teachers; and childhood maltreatment. Psychoactive substance use was found to be prevalent among adolescents in this study.