In response to stressors, individuals adopt different behavioral styles, which are essential for survival and form the basis of differential susceptibility to stress-related disorders. Corticotropin-releasing factor (CRF) and the medial prefrontal cortex (mPFC) have predominantly been studied in behavioral response to stress, while the role of mPFC CRF neurons is poorly understood. Using morphology, electrophysiology, and calcium imaging approaches, we characterized mPFC CRF neurons as a unique subtype of GABAergic inhibitory interneurons that were directly engaged in the tail suspension challenge. Genetic ablation or chemogenetic inhibition of dorsal mPFC (dmPFC) CRF neurons increased immobility under the tail-suspension and forced-swimming challenges and induced social avoidance behavior, whereas activation had the opposite effect on the same measures. Furthermore, increasing CRF neuronal activity promoted durable resilience to repeated social defeat stress. These results uncover a critical role of mPFC CRF interneurons in bidirectionally controlling motivated behavioral style selection under stress. Display omitted •Prefrontal CRF GABAergic interneurons are recruited during behavioral challenges•Manipulation of CRF neurons motivates selection of behavioral styles under challenges•Activation of CRF neurons promotes persistent stress-resistant behaviors Chen et al. identify a population of mPFC CRF neurons that form monosynaptic GABAergic inhibitory connections with pyramidal cells and play a key role in controlling behavioral style selection in the face of various stressful challenges.