Adults with mental health conditions (MHC) are especially likely to smoke and experience tobacco-related health disparities. Individuals with MHC may also use electronic nicotine delivery devices (ENDS) at disproportionately high rates. However, there is a relative dearth of knowledge regarding ENDS use among individuals with MHC. In a large representative sample of U.S. adults (n = 6051), associations between self-reported MHC diagnoses and ENDS use and susceptibility were examined, stratified by smoking status. Participants with MHC were approximately 1.5 times more likely to have used ENDS in their lifetime and almost twice as likely to currently use ENDS as those without MHC. MHC status was most strongly linked to higher ENDS use among former smokers, and former smokers with MHC were more likely to report using ENDS during past smoking quit attempts than those without MHC. Among participants who had not tried ENDS, former smokers with MHC were especially susceptible to future ENDS use. The potential advantage of ENDS for cessation purposes should be balanced with the risk of attracting former smokers with MHC to ENDS.