Background and Aim:Homelessness, as a growing public health issue, is associated with high prevalence of psychiatric disorders, substance use, sleep disturbances, and high-risk sexual behaviors. This study aimed to examine mental health status, sleep quality, high-risk sexual behaviors, and their related factors among homeless men. Methods:This cross-sectional analytical study was conducted on 239 homeless men residing in two specialized shelters and rehabilitation centers for homeless individuals in Mobarakeh County and Isfahan, Iran. Data were collected using the 28-item General Health Questionnaire (GHQ-28), the Pittsburgh Sleep Quality Index (PSQI), and a questionnaire assessing risky sexual behaviors. Demographic characteristics and patterns of substance use were obtained through semi-structured interviews. Data analysis was performed using SPSS software version 26, applying descriptive and inferential statistical tests. Results:The mean age of participants was approximately 40 years, with most aged between 30 and 50 years. About 46.4% had impaired general health, and 63.6% experienced poor sleep quality. The mean high-risk sexual behavior score was 2.48 ± 4.30. Poor general health was associated with housing instability, high-risk livelihood strategies, a history of injecting substances, and repeated attempts to quit (p<0.05). Poor sleep quality was correlated with housing status and substance use patterns. High-risk sexual behaviors were more prevalent among younger, single, and unstably housed individuals. Early initiation of substance and cigarette use was associated with poorer mental health and higher engagement in high-risk sexual behaviors. Conclusion:The findings of this study indicate that homelessness, substance use, psychological disorders, sleep disorders, and high-risk sexual behaviors operate concurrently and interactively among homeless men, influencing one another. These results underscore that improving the well-being of this population requires multidimensional interventions, including the provision of stable housing, enhancement of economic security, addiction treatment, and harm reduction strategies.