Flexible initiation or suppression of actions to avoid aversive events is crucial for survival. The prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex (mPFC) have been implicated in different aspects of avoidance and reward-seeking, but their respective contribution in instigating versus suppressing actions in aversive contexts remains to be clarified. We examined mPFC involvement in different forms of avoidance in rats well trained on different cued lever-press avoidance tasks. Active/inhibitory avoidance required flexible discrimination between auditory cues signaling foot-shock could be avoided by making or withholding instrumental responses. On a simpler active avoidance task, a single cue signaled when a lever press would avoid shock. PL inactivation disrupted active but not inhibitory avoidance on the discriminative task while having no effect on single-cued avoidance. In comparison, IL inactivation broadly impaired active and inhibitory avoidance. Conversely, on a cued appetitive go/no-go task, both IL and PL inactivation impaired inhibitory but not active reward-seeking, the latter effect being diametrically opposite to that observed on the avoidance task. These findings highlight the complex manner in which different mPFC regions aid in initiating or inhibiting actions in the service of avoiding aversive outcomes or obtaining rewarding ones. IL facilitates active avoidance but suppress inappropriate actions in appetitive and aversive contexts. In contrast, contextual valence plays a critical role in how the PL is recruited in initiating or suppressing actions, which may relate to the degree of cognitive control required to flexibly negotiate response or motivational conflicts and override prepotent behaviors.SIGNIFICANCE STATEMENT Choosing to make or withhold actions in a context-appropriate manner to avoid aversive events or obtain other goals is a critical survival skill. Different medial prefrontal cortex (mPFC) regions have been implicated in certain aspects of avoidance, but their contributions to instigating or suppressing actions remains to be clarified. Here, we show that the dorsal, prelimbic (PL) region of the medial PFC aids active avoidance in situations requiring flexible mitigation of response conflicts, but also aids in withholding responses to obtain rewards. In comparison the ventral infralimbic (IL) cortex plays a broader role in active and inhibitory avoidance as well as suppressing actions to obtain rewards. These findings provide insight into mechanisms underlying normal and maladaptive avoidance behaviors and response inhibition.