The objective of this study was to identify the correlates of being at risk of clinical depression and examine the role of syndemic factors among marginally housed and homeless transitional age youth (TAY). From 2017–2018, 100 TAY between the ages of 18 and 24 in San Francisco were recruited from Larkin Street Youth Services into a cross-sectional study. Participants completed surveys on mental health, substance use, and HIV risk behaviors. A syndemic score ranging from 0–3 was calculated by summing dichotomous measures of moderate or severe anxiety in the past two weeks, PTSD symptoms in the past month and polysubstance use in the past three months. We used modified Poisson regression with robust error variances to identify the correlates of being at risk of clinical depression in the past week, all primary effects measures were modeled separately. Among 100 participants, the average age was 21 (SD = 1.7), 67% were male, 38% were Multiracial, 54% identified as gay, lesbian, bisexual or pansexual, 13% were unstably housed, 50% were homeless and 23% were living with HIV. The majority (74%) were at risk of clinical depression, 51% had symptoms of moderate or severe anxiety, 80% exhibited symptoms of PTSD and 33% reported polysubstance use.