•Drug use disorder (DUD) is common in this population, many involving >1 drugs (22 %).•Several factors explained differences in DUD—some within- and some between-person.•Within-person changes in alcohol use quantity correspond to changes in DUD.•Peer behaviors and related factors affect DUD through between-person effects.•Parent support, violence exposure, and mental health show within-person effects. The distinction between within- and between-person associations with drug use disorder (DUD) has implications for intervention targets and content. We used longitudinal data from youth entering an urban emergency department (ED) to identify factors related to changes in DUD diagnosis, with particular emphasis on alcohol use. Research staff recruited youth age 14–24 (n = 599) reporting any past six-month drug use from a Level-1 ED; participants were assessed at baseline and four biannual follow-ups. Participants self-reported validated measurements of peer/parental behaviors, violence/crime exposure, drug use self-efficacy, and alcohol use. Research staff performed diagnostic interviews for DUD with nine substances, post-traumatic stress disorder (PTSD), and major depressive disorder (MDD). We used repeated measures logistic regression models with person-level covariate means, and person-mean-centered covariates, as separate variables, to separate within- and between-person covariate effects. Among 2,630 assessments, 1,128 (42.9 %) were DUD diagnoses; 21.7 % were co-diagnoses with multiple drugs. Positive (aOR = 0.81, 95 %CI:0.70, 0.94) and negative (aOR = 1.73, 95 %CI:1.45, 2.07) peer behaviors related to DUD, primarily through between-person effects. Parental support (aOR = 0.92, 95 %CI:0.83, 0.99), community violence/crime (aOR = 1.28, 95 %CI:1.14, 1.44), PTSD/MDD diagnosis (aOR = 1.36, 95 %CI:1.04, 1.79), and alcohol use quantity (aOR = 1.06, 95 %CI:1.02, 1.11) were associated with DUD, showing primarily within-person effects. Other factors, such as interpersonal violence involvement (aOR = 1.47, 95 %CI:1.21, 1.78), showed both within- and between-person effects. DUD is prevalent in this population, and within-person changes in DUD are predictable. Within-person effects suggest the importance of addressing escalating alcohol use, enhancing parental support, crime/violence exposure, and other mental health diagnoses as part of DUD intervention.