Background: Substance use among adolescents, especially smoking and alcohol consumption, has become a public health concern in the Kurdistan Region, Iraq, in the past 10 years. Aims: This study aimed to determine the prevalence of substance use and certain associated factors among high school students in Erbil City, Kurdistan Region, Iraq. Methods: A cross-sectional study was conducted using a multistage cluster sampling technique to collect a sample of 3000 students. A modified version of the School Survey on Drug Use from the United Nations Office on Drugs and Crime was used for data collection. Binary logistic regression models were used to identify risk factors for substance use. Results: The lifetime prevalence rates of cigarettes smoking, waterpipe smoking and alcohol consumption were 27.6%, 23.6% and 3.7%, respectively. Male gender, age 17-19 years, smoker in the family, and easy accessibility of cigarettes were significantly associated with cigarette smoking. Factors significantly associated with waterpipe smoking were male gender, age 17-19 years, waterpipe smoker in the family, waterpipe smoker friend, and easy accessibility. Male gender, alcohol dependent in the family, alcohol-dependent friend, easy accessibility of alcohol, and low family income were significant predictors of alcohol consumption. Conclusions: The prevalence of cigarette smoking and waterpipe use was high in the studied sample. Possible explanations for this finding might be the use of flavoured tobacco associated with aromatic smell, and the misconception that waterpipe smoking is less toxic and addictive than cigarette smoking.