Breaking bad news (BBN; i.e., the disclosure of a serious diagnosis) is a necessary but challenging task in the medical field, often raising stress levels among physicians. According to the biopsychosocial model of challenge and threat, stress responses can manifest as adaptive challenge states or maladaptive threat states. Prior research has proposed that specific patterns in neuroendocrine responses may signal challenge and threat. In this study, we employed a 2 × 2 design to examine the effects of stress arousal reappraisal (SAR; i.e., reframing bodily arousal as a functional response) and worked example (WE; i.e., stepwise demonstration of BBN) interventions on salivary cortisol, dehydroepiandrosterone, and alpha-amylase responses. A total of 229 third-year medical students participated in a BBN simulation. While significant activation (rise) and regulation (decline) of neuroendocrine markers were observed in response to the BBN encounter, neither the SAR nor the WE intervention affected their peak levels or the magnitude (area under the curve) of the response. Only the WE intervention decelerated the rise and decline in dehydroepiandrosterone levels around individual peaks, potentially indicating an attenuated stress response. These findings suggest that neither of the interventions induced the expected challenge pattern in neuroendocrine activity. However, due to the low temporal resolution of salivary measurements and the dynamic process of challenge and threat orientations, we propose that the neuroendocrine responses may have limitations in distinguishing between challenge and threat.