BACKGROUND: Stress-related disruption of emotion regulation appears to involve the prefrontal cortex (PFC) and amygdala. However, the interactions between brain regions that mediate stress-induced changes in emotion regulation remain unclear. The present study builds upon prior work that assessed stress-induced changes in the neurobehavioral response to threat by investigating effective connectivity between these brain regions. METHODS: Participants completed the Montreal Imaging Stress Task followed by a Pavlovian fear conditioning procedure during functional magnetic resonance imaging. Stress ratings and psychophysiological responses were used to assess stress reactivity. Effective connectivity during fear conditioning was identified using multivariate autoregressive modeling. Effective connectivity values were calculated during threat presentations that were either predictable (preceded by a warning cue) or unpredictable (no warning cue). RESULTS: A neural hub within the dorsomedial PFC (dmPFC) showed greater effective connectivity to other PFC regions, inferior parietal lobule, insula, and amygdala during predictable than unpredictable threat. The dmPFC also showed greater connectivity to different dorsolateral PFC and amygdala regions during unpredictable than predictable threat. Stress ratings varied with connectivity differences from the dmPFC to the amygdala. Connectivity from dmPFC to amygdala was greater in general during unpredictable than predictable threat, however, this connectivity increased during predictable compared to unpredictable threat as stress reactivity increased. CONCLUSIONS: Our findings suggest that acute stress disrupts connectivity underlying top-down emotion regulation of the threat response. Furthermore, increased connectivity between the dmPFC and amygdala may play a critical role in stress-induced changes in the emotional response to threat.