Self-affirmation can buffer stress responses across different contexts, yet the neural mechanisms for these effects are unknown. Self-affirmation has been shown to increase activity in reward-related neural regions, including the ventral striatum and ventromedial prefrontal cortex (VMPFC). Given that reward-related prefrontal cortical regions such as the VMPFC are involved in reducing neurobiological and behavioral responses to stress, we hypothesized that self-affirmation would activate VMPFC and also reduce neural responses to stress in key neural threat system regions such as the dorsal anterior cingulate cortex (dACC) and anterior insula (AI). We explored this hypothesis using self-affirmation and evaluative stress tasks following a within-subjects design in the fMRI scanner. Consistent with prior work, self-affirmation blocks led to lower self-reported stress and improved performance. With respect to neural activity, compared to control blocks, self-affirmation blocks led to greater VMPFC activity, and subsequently less left AI (but not dACC) activity during stress task blocks. Functional connectivity analyses revealed greater connectivity between the VMPFC and left and right AI during self-affirmation compared to control. These findings begin to articulate the neural circuits involved in self-affirmation's effects during exposure to stressors, and more broadly specify neural reward-based responses to stressful situations.