Understanding pathways of risk following a natural disaster may help create next-generation targeted interventions. The current study examined if a biomarker of cognitive-affective response (pupil dilation) could identify which individuals are at greatest risk for depression following disaster-related stress. Fifty-one women completed a computer-based task assessing pupillary response to facial expressions of emotion and reported their depressive symptoms before the 2011 Binghamton flood. Following the flood, women were assessed for objective levels of flood-related stress and again reported their depressive symptoms. Supporting the proposed diathesis-stress model, decreased pupil dilation to emotional expressions predicted a significant increase in post-flood depressive symptoms, but only among women who experienced higher levels of flood-related stress. Findings suggest that reduced cognitive-affective response to emotional stimuli (measured via pupillary response) can increase risk for depression in the context of high levels of objective life stress.