Objective: Violence is a leading cause of death among individuals ages 18-25, with alcohol misuse consistently linked with violence perpetration. However, the association between polysubstance use and violence perpetration is less clear, despite the frequency of use of alcohol with other drugs. Additionally, protective factors such as mindfulness that may reduce violence perpetration among emerging adults have been understudied. This cross-sectional study examined the association between substance use, trait mindfulness, and violence perpetration outside of romantic relationships, utilizing a compensatory model of resilience. Methods: Data were drawn from a sample of 665 emerging adults ages 18-25, recruited from an urban Emergency Department (68% men). Participants self-administered a computer survey that assessed non-partner violence perpetration (NPV), alcohol use, marijuana use, prescription drug misuse, and trait mindfulness. Fifteen percent reported non-partner violence perpetration over the past six months. Results: Multivariate logistic regression tested associations between violence perpetration, substance use, trait mindfulness, and demographic characteristics. Results showed that alcohol use alone (OR= 3.04), prescription opioid use alone (OR = 3.58), alcohol and marijuana use (OR = 3.75), and use of all three substances (OR= 7.78) were positively associated with violence perpetration. Post-hoc contrasts demonstrated the polysubstance use significantly increased risk over single substance use. Trait mindfulness (OR= 0.97) was negatively associated with violence perpetration after controlling for substance use. Conclusions: Findings suggest that polysubstance use may increase risk for violence. Interventions that address polysubstance use, potentially including mindfulness, could reduce non-partner violence perpetration among emerging adults and requires further study.