Undergraduate nursing students show high-stress levels. In students, stress has been linked to adverse physical and psychological health outcomes and academic and clinical demands. To date, there are few studies dealing with psychological predictors of stress amongst nursing students. This study aimed to assess psychological distress in a sample of Italian nursing students and to explore its relationship with sociodemographic and psychological factors, specifically dispositional mindfulness, emotional regulation difficulties, and empathy. A multicenter cross-sectional survey design was employed. Participants were recruited from five teaching hospitals associated with a public university in northern Italy. A sample of 622 undergraduate nursing students was recruited. Participants were recruited on campus and completed a paper-and-pencil survey. More than 70% of nursing students reported meaningful levels of psychological distress. Students with higher dispositional mindfulness scores had lower psychological distress, whereas emotional regulation difficulties and empathic personal distress were positively associated with perceived stress. No gender differences were found in stress levels, but senior students showed lower psychological distress than more junior students. Interventions aimed at increasing mindfulness facets and improving emotional regulation strategies may help to reduce perceived psychological stress in nursing students.