Substance abuse is a major concern worldwide and is increasing rapidly in Bangladesh. However, there are no prior studies concerning lifestyle-related factors that influence adolescents’ substance use behavior. Therefore, the present study investigated the prevalence of substance use and its associated sociodemographic and lifestyle-related risk factors among a total of 424 Bangladeshi high school-going adolescents through a structured questionnaire interview study. The survey questionnaire consisted of socio-demographics, lifestyle-related information, and substance use-related questions. For data analysis, descriptive and inferential statistics were performed using SPSS (Statistical Package for Social Science) version 22.0, and a p-value of <0.05 determined statistical significance. Results showed that 21.2%, 14.4%, and 15.1% of the participants reported smoking, using a drug, and consuming alcohol, respectively, at least once during their lifespan; whereas the current (i.e., past-month) rates were reported to be 10.4%, 2.8%, and 3.1%, respectively. Overall, the current substance use risk factors were identified as being male, not being from science academic background, having less family influence on personal life, irregular teeth brushing, being smartphone users, using a smartphone for a longer time, and being late-night sleepers. From the list of identified risk factors of substance use, those that are modifiable may be targeted to evolve a prevention program to manage this problem in Bangladeshi adolescents.