Afghanistan provides a unique setting in which to appraise psychosocial stress, given the context of persistent insecurity and widening economic inequality. In Kabul, people experience widespread frustrations, hinging on restricted opportunities for social advancement, education, and employment. We appraised social aspirations, every-day stressors, psychosocial distress, and mental health problems for a random sample of 161 male and female students at Kabul University. The survey featured both existing and newly-developed instruments (Self-Reported Questionnaire SRQ-20; Afghan Symptom Checklist; Afghan Daily Stressor Scale; and Social Aspirations and Frustrations), implementing both internationally-used and culturally-grounded measures of mental health assessment. We also included indicators of physical health (blood pressure, immune responses to Epstein-Barr virus (EBV), C-reactive protein, and body mass index), to map physiological function with reported psychosocial distress. This young, urban elite expressed major feelings of frustrations, related to physical, economic, social, and political stressors of day-to-day life in Kabul. There were striking gender differences for psychosocial and physiological markers of wellbeing; specifically, women showed poorer mental health (SRQ-20, P = 0.01) and elevated EBV antibody titers (P = 0.003). Both diastolic blood pressure (P = 0.018) and EBV (P = 0.038) were associated with a subscale of family stressors among women, but not among men, consistent with women’s social vulnerabilities to stressful family dynamics. This is the first study to integrate approaches from anthropology, cross-cultural psychiatry, and human biology to document social stressors, psychosocial distress, and physiological wellbeing in the challenging setting of present-day Afghanistan.