Introduction: Youth and young adults with asthma use electronic cigarettes (e-cigarettes) at a higher rate than those without asthma. However, the factors that influence e-cigarette use in this vulnerable population are scarce. Therefore, the study aim was to assess the effects of anxiety, depression, impulsivity, and substance use in the relationship between e-cigarette use and youth and young adults with asthma status. Method: We enrolled youth and young adults (15-25 years old) in Alabama with a clinical diagnosis of asthma (n = 151) or without a diagnosis of any chronic pulmonary disease (n = 132; reference group). Validated questionnaires were administered to collect demographic data and assess susceptibility to e-cigarette use, current use of e-cigarettes, anxiety, depression, impulsivity, and substance use (alcohol and cannabis). We then conducted parallel mediation analyses to test the mediational effects of anxiety, depression, and impulsivity, and moderation analyses to assess the moderation effects of substance use in the relationship between asthma and e-cigarette use. Results: Susceptibility to e-cigarette use and current use of e-cigarettes were both lower among youth and young adults with asthma. After controlling for covariates, anxiety, depression, and impulsivity were not significant mediators of the relationships between asthma and susceptibility to e-cigarette use and current use of e-cigarettes. However, the frequency of cannabis use in the past 30 days moderated the relationship between asthma and susceptibility to e-cigarette use (Unstandardized beta = − 2.03, p = 0.046), such that more frequent cannabis use was associated with less susceptibility. Conclusion: Among youth and young adults with asthma, cannabis use was associated with reduced susceptibility to e-cigarette use. Longitudinal assessments of this population are needed to better assess the temporal relationship between asthma, comorbid substance use, and e-cigarette use among young people with asthma to avoid pulmonary complications.