Thoughts of death substantially influence human behavior and psychological well-being. A large number of behavioral studies have shown evidence that asking individuals to think about death or mortality salience leads to significant changes of their behaviors. These findings support the well-known terror management theory to account for the psychological mechanisms of existential anxiety. However, despite increasing findings of mortality salience effects on human behavior, how the brain responds to reminders of mortality and changes the activity underlying subsequent behavior remains poorly understood. By scanning healthy adults (N = 80) of both sexes using functional magnetic resonance imaging, we showed that, relative to reading emotionally neutral sentences, reading sentences that evoke death-related thoughts decreased the salience network activity, reduced the connectivity between the cingulate cortex and other brain regions during a subsequent resting state, and dampened the speed of learning reward-related objects and cingulate responses to loss feedback during a subsequent reward learning task. In addition, the decreased resting-state cingulate connectivity mediated the association between salience network deactivations in response to reminders of mortality and suppressed cingulate responses to loss feedback. Finally, the suppressed cingulate responses to loss feedback further predicted the dampened speed of reward learning. Our findings demonstrate sequential modulations of the salience network activity by mortality salience, which provide a neural basis for understanding human behavior under mortality threat.