Interactions between the medial prefrontal cortex (PFC) and higher-order thalamus play a critical role in cognitive behaviors and are disrupted in neuropsychiatric disorders. Here we find that layer 6 (L6) cortico-thalamic (CT) neurons in the PFC make excitatory connections onto both mediodorsal (MD) and ventromedial (VM) thalamus. We examine how these neurons evoke activity in vivo, with a mix of direct excitation and feed-forward inhibition in MD, but excitation alone in VM. This reflects unexpected connectivity in the anterior thalamic reticular nucleus (TRN), with PFC inputs primarily contacting MD-projecting neurons, while avoiding VM-projecting neurons. Together, our findings highlight the TRN as a critical node for regulating the balance of excitation and inhibition in higher-order thalamus.