With the ever-changing social environment, individual creativity is facing a severe challenge induced by stress. However, little is known about the physiological mechanisms by which acute stress affects creative cognitive processing. The current study explored the effects of neuroendocrine response on creativity under stress and its underlying cognitive flexibility mechanisms. The Enzyme-Linked Immuno Sorbent Assay was used to assess salivary cortisol, which acted as a marker of stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Eye blink rate (EBR) and pupil diameter were measured as respective indicators of dopamine and noradrenaline released by activation of the sympathetic-adrenal medullary (SAM) axis. The Wisconsin Card Task (WCST) measured cognitive flexibility, while the Alternative Uses Task (AUT) and the Remote Association Task (RAT) measured separately divergent and convergent thinking in creativity. Results showed higher cortisol increments following acute stress induction in the stress group compared to the control group. Ocular results showed that the stress manipulation significantly increased EBR and pupil diameter compared to controls, reflecting increased SAM activity. Further analysis revealed that stress-released cortisol impaired the originality component of the AUT by increasing perspective errors of the WCST. Serial mediation analyses showed that both EBR and pupil diameter were also associated with increased perspective errors leading to poor originality on the AUT. These findings confirm that physiological arousal under stress can impair divergent thinking through the regulation of different neuroendocrine pathways, in which the deterioration of flexible switching plays an important mediating role.