Contemporary environments are saturated with food cues that stimulate appetites in the absence of hunger, which leads to maladaptive eating. These settings can induce persistent drive to eat, as learned behaviors can reappear after extinction. Behavioral paradigms of responding renewal provide a valuable framework to study how food cues contribute to the inability to resist palatable foods and change maladaptive eating habits. Using a rat model for this persistent food motivation, we determined sex differences in the causal function for the ventromedial prefrontal cortex (vmPFC) during context-mediated renewal of responding to food cues. Previously, we found behavioral sex differences (only males exhibited renewal) and differential recruitment within the vmPFC (increased Fos induction in males but decreased in females). Here, we used DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to silence vmPFC neurons in males and to stimulate vmPFC neurons in females specifically during renewal. Silencing vmPFC neurons in males disrupted renewal of responding to a food cue, while stimulating vmPFC neurons in females induced this behavior. These findings demonstrate sex differences in the vmPFC function in a model of food seeking relevant to environmentally driven appetites contributing to obesity and eating disorders.