Introduction: The effects of the COVID-19 pandemic have been dramatic and wide-reaching, affecting many more than those who become ill, including reports of increased substance use among adolescents may be due to various restrictions of social life that disrupted adolescents’ daily lives. However, up to now, no data is showing the extent of substance use among adolescents in the study area. This study aimed to assess the prevalence of substance use and associated factors during the Covid-19 pandemic among school adolescents of west hararghe, Eastern Ethiopia to guide possible intervention and public policy. Methods: A School-based cross-sectional study design was conducted from 10 to 30, October 2021. A multi-stage sampling technique was used to select 788 students from ten public secondary schools in the West Hararge zone, Eastern Ethiopia. The data were collected using a self-administered pre-tested semi-structured questionnaire. Data was entered into Epidata version 3.1 and then exported to SPSS version 26 software for further analysis. Descriptive analysis was done. Multi variables binary logistic regression was done and a p-value less than 0.05 were used to declare statistical significance. Results : In this study, the response rate of 98.46% were complete fill the questionnaires. More than 1 in 2 of the adolescent students were self-reported substances (alcohol, khat (Catha edulis) and/or cigarette) users (prevalence = 58.6%) during the Covid-19 pandemic. Specifically, chewing khat (Catha edulis) (57.87%), followed by alcohol user (21.73%), Cigarette smoking (14.85%) and, hashish consumption (5.54%).  Age of students, family history of drinking alcohol, availability of substances were factors positively associated with substance use. On the other hand, family management is negatively associated with substance use. Conclusions: The prevalence of substance users among adolescents was dramatically increased during the covid-19 pandemic in the west hararghe zone, Ethiopia. Hence, the authors hoped that these findings provide preliminary insights for refining mental health and addiction policies that are targeted at adolescent and their parents in these settings and guidance for further research.