BACKGROUND: Nursing internship play a crucial role in cultivating nursing students. However, nursing interns often face challenges of career anxiety, which can have negative impacts on their professional development and work quality. Therefore, understanding the factors influencing career anxiety among nursing interns is important. OBJECTIVES: The purpose of this study was to investigate the serial multiple mediating effect of perceived stress and self-control in the relationship between neuroticism and career anxiety among nursing interns in China. DESIGN: A cross-sectional study. METHODS: A total of 499 nursing interns from five tertiary hospitals in Xi'an, China, participated. Neuroticism, perceived stress, self-control, and career anxiety among nursing interns were assessed. Serial mediation analysis was conducted using the PROCESS Macro in SPSS. Statistical analyses included descriptive analysis, t-tests, ANOVA, Pearson correlation, and regression with bootstrapping. RESULTS: (1)Career anxiety was significantly and positively correlated with neuroticism (r = 0.384, p <
0.001) and perceived stress (r = 0.460, p <
0.001), and negatively correlated with self-control (r = -0.570, p <
0.001). (2) Neuroticism positively predicted perceived stress (β = 0.385, p <
0.001). Both perceived stress and neuroticism, negatively predicted self-control (β = -0.237
β = -0.355, p <
0.001). Self-control negatively predicted career anxiety (β = -0.401, p <
0.001), while neuroticism and perceived stress positively predicted it (β = 0.149
β = 0.173, p <
0.001). (3) In the model of neuroticism → perceived stress → self-control → career anxiety, the total indirect effect was 0.216. The mediating effect of perceived stress accounted for 18.1% of the total effect (0.066), while self-control accounted for 26.0% (0.095). The serial mediation effect of perceived stress and self-control contributed 15.1% (0.055) to the total effect. CONCLUSION: Neuroticism significantly predicts career anxiety, mediated by perceived stress and self-control. Higher neuroticism leads to increased stress, reduced self-control, and greater career anxiety. Interventions focusing on stress reduction and self-control enhancement may help mitigate career anxiety among nursing interns. CLINICAL TRIAL NUMBER: Not applicable.