Substance use often begins during adolescence, placing youths at risk for fatal overdose and substance use disorders (SUD) in adulthood. Understanding the motivations reported by adolescents for using alcohol, marijuana, and other drugs and the persons with whom they use these substances could guide strategies to prevent or reduce substance use and its related consequences among adolescents. A cross-sectional study was conducted among adolescents being assessed for SUD treatment in the United States during 2014-2022, to examine self-reported motivations for using substances and the persons with whom substances were used. The most commonly reported motivation for substance use was "to feel mellow, calm, or relaxed" (73%), with other stress-related motivations among the top reasons, including "to stop worrying about a problem or to forget bad memories" (44%) and "to help with depression or anxiety" (40%); one half (50%) reported using substances "to have fun or experiment." The majority of adolescents reported using substances with friends (81%) or using alone (50%). These findings suggest that interventions related to reducing stress and addressing mental health concerns might reduce these leading motivations for substance use among adolescents. Education for adolescents about harm reduction strategies, including the danger of using drugs while alone and how to recognize and respond to an overdose, can reduce the risk for fatal overdose.