In the murine sensorimotor cortex, Drd1a-Cre+ neurons in layer 6b project to higher-order thalamic nuclei and are the only cortical projection neurons responsive to the wake-promoting neuropeptide orexin, suggesting that L6-Drd1a neurons play an important role in sensory processing, brain state modulation, attention, and cognition (Hoerder-Suabedissen et al., 2018; Zolnik et al., 2023). In the medial prefrontal cortex (mPFC), whether these neurons play an analogous role in gating cortical arousal remains poorly understood. Thus, we investigated the effects of ‘silencing’ L6-Drd1a neurons in a conditional Snap25 KO mouse model (Drd1a-Cre+/-;Snap25fl/fl) on the dopaminergic modulation of network activity in mPFC acute brain slices using planar high-density multielectrode arrays (MaxWell Biosystems) and patch clamp recordings. In WT slices, we found a significant increase in delta activity and evoked network spiking in the infralimbic mPFC after D1 receptor agonist SKF-81297 administration, which was eliminated upon chronic silencing of L6-Drd1a neurons. Application of the D2 receptor agonist quinpirole had no effect in WT slices, but chronically silencing L6-Drd1a neurons unmasked a quinpirole-induced increase in delta activity and evoked network spiking in the infralimbic mPFC, suggesting that L6-Drd1a neurons mediate an inhibitory effect of D2 receptor activation and/or a compensatory shift in D2 receptor function. We followed up these findings with whole-cell electrophysiological characterization of these L6-Drd1a neurons. Our results provide novel insight into the dopaminergic modulation of L6-Drd1a neurons in the mPFC that may contribute to their orexinergic response in mediating attention and arousal, with relevant therapeutic implications for stress-related neurodevelopmental disorders.