Post-traumatic stress disorder (PTSD) is associated with increased risk for polydrug use. Low self-control is a key characteristic of the disorder and is predictive of polydrug use. However, there is a dearth of research focused on the relevance of a dual systems model delineation of self-control into the constructs of risk-seeking and impulsivity as it pertains to polydrug use and PTSD. This study tested dual systems mediation of this relationship. Generalized structural equation modeling was used to test for mediation effects. Results indicated that more PTSD symptoms predicted increased drug use variety (coefficient = 0.024; confidence interval [CI] = [0.001, 0.046]). Inclusion of dual systems constructs fully attenuated this relationship. The total indirect effect achieved marginal significance (coefficient = 0.005; CI = [>−0.001, 0.009]). Sensitivity analyses of the specific indirect effect of impulsivity as the sole mediator indicated significant mediation. These results provide some indication that impulsivity-based programming may help to treat polydrug use among those with severe PTSD.