Homeless persons are victims of violent and non-violent crime at higher rates than housed populations. While studies have suggested that victimization can induce or exacerbate mental health problems, there is very little known about factors that may buffer the effects of victimization. This cross-sectional study examined the influence of victimization on depressive symptoms in over 9600 homeless and mentally ill adults participating in the Access to Community Care and Effective Services and Supports study (ACCESS) conducted in multiple cities across the USA relationships between victimization, depressive symptoms, and perceived safety were tested within a structural equation modeling framework using data collected at the baseline interview. The overall model exhibited a good fit with the data. Non-physical victimization was associated with higher levels of depressive symptoms, and physical victimization was associated with lower levels of perceived safety. As hypothesized, perceived safety was a significant partial mediator of depressive symptoms. These results underscore the complexity of the relationships between victimization and depression in homeless adults and the importance of addressing different types of victimization in homeless and mentally ill adults.