Youth and adolescent psychoactive substance use is a major public health problem worldwide which affects the health of individuals, families, and the community as a whole. This study was aimed at assessing the level of psychoactive substance use and the associated factors among the youths of North Sowa zone, Amhara region, Ethiopia, 2020/21. Community based cross-sectional study design with a multistage sampling technique was used. A total of 632 youths were involved in the study. Linear logistic regression analysis was used for both bivariate and multivariate analysis. The prevalence of life time and current psychoactive substance use was found to be 66.1% and 65%, respectively. Male sex and history of substance use from family members and friends were significantly associated with psychoactive substance use. In this study, the prevalence of life time and current psychoactive substance use was high as compared to other studies conducted in Ethiopia.