The brain stem nucleus locus coeruleus (LC) is thought to modulate cortical excitability by norepinephrine (NE) release in LC forebrain targets. The effects of LC burst discharge, typically evoked by a strong excitatory input, on cortical ongoing activity are poorly understood. To address this question, we combined direct electrical stimulation of LC (LC-DES) with extracellular recording in LC and medial prefrontal cortex (mPFC), an important cortical target of LC. LC-DES consisting of single pulses (0.1–0.5 ms, 0.01–0.05 mA) or pulse trains (20–50 Hz, 50–200 ms) evoked short-latency excitatory and inhibitory LC responses bilaterally as well as a delayed rebound excitation occurring ∼100 ms after stimulation offset. The pulse trains, but not single pulses, reliably elicited mPFC activity change, which was proportional to the stimulation strength. The firing rate of ∼50% of mPFC units was significantly modulated by the strongest LC-DES. Responses of mPFC putative pyramidal neurons included fast (∼100 ms), transient (∼100–200 ms) inhibition (10% of units) or excitation (13%) and delayed (∼500 ms), sustained (∼1 s) excitation (26%). The sustained spiking resembled NE-dependent mPFC activity during the delay period of working memory tasks. Concurrently, the low-frequency (0.1–8 Hz) power of the local field potential (LFP) decreased and high-frequency (>20 Hz) power increased. Overall, the DES-induced LC firing pattern resembled the naturalistic biphasic response of LC-NE neurons to alerting stimuli and was associated with a shift in cortical state that may optimize processing of behaviorally relevant events.