There is increasing interest in understanding how active learning affects students’ mental health as science courses transition from traditional lecture to active learning. Prior research has found that active learning can both alleviate and exacerbate undergraduate mental health problems. Existing studies have only examined the relationship between active learning and anxiety. No studies have examined the relationship between active learning and undergraduate depression. To address this gap in the literature, we conducted hour-long exploratory interviews with 29 students with depression who had taken active learning science courses across six U.S. institutions. We probed what aspects of active learning practices exacerbate or alleviate depressive symptoms and how students’ depression affects their experiences in active learning. We found that aspects of active learning practices exacerbate and alleviate students’ depressive symptoms, and depression negatively impacts students’ experiences in active learning. The underlying aspects of active learning practices that impact students’ depression fall into four overarching categories: inherently social, inherently engaging, opportunities to compare selves to others, and opportunities to validate or invalidate intelligence. We hope that by better understanding the experiences of undergraduates with depression in active learning courses we can create more inclusive learning environments for these students.