So called third culture kids (TCKs), the children and adolescents who accompany their parents on long-term overseas work assignments, often have to face life changes, cultural challenges and threats to social identity. The frequency, intensity and nature of these challenges arguably places some TCKs at heightened risk of stress-related mental health problems. Trait mindfulness, an attribute that can be enhanced through intervention, has been found to buffer against stress reactivity and common mental health problems. This study aims to explore the relationship between stress reactivity, trait mindfulness and depressive symptomatology among expatriate adolescents (TCKs) attending an international school in the United Arab Emirates (UAE). Participants included 230 high school students (57% female) from 45 different nations, with a mean age of 15.5 (±1.3, 12–19). Forty one percent had lived in the UAE for 7+ years. Participants completed measures of trait mindfulness, daily life stress reactivity, and depressive symptoms (CES-D). Mean depression score was high with 68.7% of TCK participants presenting as at risk of clinical depression. Lower stress-reactivity and greater trait mindfulness were associated with lower levels of depression; furthermore, low levels of trait mindfulness partially mediated the relationship between stress reactivity and depression. Efforts that aim to reduce stress reactivity and increase mindfulness might prove especially beneficial among the TCK population.