ObjectivesThe current study examines the mediating roles of resilience and self-efficacy and the moderating role of gender in the association between neuroticism and psychological distress in Chinese freshman nursing students (FNSs).MethodsA total of 1220 FNSs were enrolled from the Be Resilient to Nursing Career (ChiCTR2000038693) Programme and the following instruments were administered to them: NEO Five-Factor Inventory, General Self-Efficacy Scale, Connor-Davidson Resilience Scale and Kessler Psychological Distress Scale. A moderated mediation analysis and a generalised additive model analysis were performed.ResultsThe direct and indirect effects of neuroticism on psychological distress were significantly mediated by self-efficacy (B = 0.200, 95% CI 0.001 to 0.039), resilience (B = 0.021, 95% CI 0.007 to 0.038) and the interaction between self-efficacy and resilience (B = 0.016, 95% CI 0.005 to 0.028). The interactions between neuroticism and gender (β = 0.102, 95% CI 0.001 to 0.203, p<0.05) and between resilience and gender were significant (β = 0.160, 95% CI 0.045 to 0.275, p<0.01). A non-linear and positive association was confirmed between neuroticism and psychological distress.ConclusionsSelf-efficacy and resilience significantly mediate the relationship between neuroticism and psychological distress. Gender moderates the relationships between neuroticism and resilience and between resilience and psychological distress.