Background <p>Young women in Kampala’s urban slums face a growing public health crisis as mental health issues and substance use escalate, fueled by poverty, violence, and limited access to care. These overlapping challenges significantly heighten the risks of suicide, premature mortality, and diminished quality of life. This study investigates the prevalence of mental health concerns, substance use, and their co-occurrence among this vulnerable population in Kampala, Uganda.</p> Methods <p>Data were drawn from the ongoing TOPOWA study, involving 300 women recruited via convenience sampling in 2023 from three study sites (i.e., Banda, Bwaise, and Makindye). Baseline assessments examined the prevalence and associations between mental health outcomes (i.e., anxiety, depression, suicidality), substance use (i.e., alcohol, drugs), and self-rated mental health (SRMH).</p> Results <p>Depression (57.7%) was the most prevalent mental health condition, followed by suicidality (46.0%) and anxiety (34.7%). The prevalence of alcohol and drug use were 27.7% and 10.7%, respectively. More than two-fifths (45.7%) reported multiple mental health conditions, which increased the likelihood of substance use. Low SRMH was significantly higher among women with anxiety, depression, suicidality, and drug use, although alcohol use alone was not significantly associated with low SRMH.</p> Conclusion <p>Mental health concerns and comorbidity were commonly noted among the young women and were strongly associated with substance use. These findings highlight the need for integrated mental health interventions to address the complex challenges faced by young women in Kampala’s slums, and especially the impact of comorbidity on mental health satisfaction.</p>