Introduction. Substance use in adolescents is a health problem that requires special attention because of the implications for their physical, mental and social development. Adolescents who experience high levels of stress and lack emotional support are more likely to resort to drug use. Emotional regulation plays a crucial role in how young people manage stress and anxiety. Those with difficulty managing their emotions may be more likely to use drugs as an escape mechanism. Purpose. To analyze the association between stressful life events, emotional regulation and substance use. Method. Six thousand six hundred thirty-seven school-aged adolescents with a mean age of 15.77 (SD ±0.8) participated, 56.8% were female, most reported living in a nuclear family (68.6%). Results. Thirty-one percent of the participants reported community violence, 20% reported emotional abuse, and 18% reported mental illness of a family member. Thirty-four percent reported moderate to severe substance use. There was a significant association between all types of stressful events and substance use (p < .001). Also, users showed a higher number of stressful events (p < .001) and significantly lower levels of attention, clarity and emotional repair (p < .001). In the regression analysis it was observed that people with inadequate emotional clarity OR=1.25, 95% CI [1.03, 1.52] and a greater number of stressful events OR=1.38, 95% CI [1.34, 1.43] have a higher probability of substance use. Conclusions. People with substance use present more stressful events compared to those who do not use substances and present inadequate emotional regulation. Interventions aimed at emotional regulation in adolescents are recommended.