Background: Asthma is associated with a greater likelihood of e-cigarette use among young adults, which may increase the risk of pulmonary complications. Because substance use trajectories emerge in early adulthood, it is important to identify factors that may be important in addressing this new public health threat. One such factor may be poor mental health. Methods: Data were extracted from the 2018 Behavioral Risk Factor Surveillance System (BRFSS). Current and former asthma status was measured by self-reported lifetime and current asthma status; mental health functioning was measured by the number of self-reported bad mental health days during the past 30 days; e-cigarette use was measured by self-reported current e-cigarette use. We tested the hypothesis that mental health mediates the association between asthma status and e-cigarette use among young adults using structural equation modeling. Results: The prevalence of e-cigarette use was significantly higher among young adults with current (9.90%) or former asthma (13.09%) than those without asthma (9.58%). Furthermore, the number of bad mental health days in the past 30 days was significantly greater among young adults with current or former asthma than among those without asthma (Mean (Standard Deviation): 6.85 (0.42), 4.18 (0.85) versus 3.83 (0.17)), respectively. Finally, we found a statistically significant indirect effect of asthma on the likelihood of e-cigarette use through mental health such that the higher prevalence of e-cigarette use among those with current or former asthma was statistically accounted for by a greater number of bad mental health days in the past 30 days. Conclusions: Consistent with mediation, poorer mental health accounted for the higher prevalence of e-cigarette use among those with asthma. However, longitudinal studies are needed to interrogate causal relationships, including the effects of e-cigarette use on mental health. Mental health services may play an important role in improving health and wellbeing in this vulnerable population.