Background: Substance use disorders and homelessness are two closely related behavioral health issues. This study examines associations between homelessness and severity of substance use disorder (SUD) characteristics (inclusive of alcohol and other legal and illegal drugs) and presence of mental health comorbidity among individuals entering treatment for SUD. We also examine differences in SUD and mental health comorbidity by gender within a sample of clients experiencing homelessness upon admission to treatment. Methods: Using the 2017 Treatment Episodes Data Set, we used logistic regression models to examine the association between homelessness and indicators of severity (e.g., frequency of use, route of transmission) and the presence of mental health conditions, and to examine the association between gender and these dependent variables among only individuals experiencing homelessness at treatment admission. Results: After controlling for covariates, homelessness is significantly associated with increased odds of cocaine and methamphetamine use compared to all other substances, higher frequency of use, younger age of first use, use of more substances, injection drug use, and co-occurring mental health conditions. Female gender is inversely associated with younger age at first use and highly associated with co-occurring mental health conditions among those experiencing homelessness at admission to treatment. Conclusions: Individuals experiencing homelessness enter substance use services with different characteristics of substance use disorders, different patterns of use, and with higher rates of mental health comorbidity. Within homeless admissions, women have significant differences in substance use and higher likelihood of mental health comorbidity than men. Future research should focus on the specific treatment needs of individuals experiencing homelessness, and how the combination of homelessness and gender affects barriers and challenges to treatment.