Objectives <p>Our study aims to identify social and behavioral factors associated with the sole-, dual-, and poly-substance use of cannabis, electronic cigarettes (ECs), and combustible tobacco among Illinoisan adolescents during the period when medical and recreational marijuana use have both been legalized.</p> Methods <p>Data came from the 2022 Illinois Youth Survey (IYS, administered to 8th-, 10th-, and 12th-grade adolescents). Multinomial regression models were used to estimate the associations between social, environmental, and behavioral characteristics and substance use patterns of sole-, dual-, and poly-substance use.</p> Results <p>After adjusting for demographics, self-reported feelings of depression, experiencing bullying at school, self-perceived school being unsafe, having peer pressure, and alcohol use were significantly associated with higher likelihood of sole-, dual-, and poly-substance use, respectively, compared with no substance use at all. Having better academic performance, having family rules on substance use, living in urban areas or more economically affluent areas significantly reduced the likelihood of sole-, dual-, or poly-substance use.</p> Conclusions <p>Our study identified several social, environmental, and behavioral factors associated with adolescent substance use. Findings may inform program designs, prevention strategies, and clinical screening to tackle adolescent substance use.</p>