Leao’s spreading depression of cortical activity is a propagating silencing of neuronal activity resulting from spreading depolarization (SD). We evaluated the contributions of action potential (AP) failure and adenosine A1 receptor (A1R) activation to the depression of evoked and spontaneous electrocorticographic (ECoG) activity after SD in vivo, in anesthetized mice. We compared depression with SD-induced effects on AP-dependent transmission, and synaptic potentials in the transcallosal and thalamocortical pathways. After SD, APs recovered rapidly, within 1–2 min, as demonstrated by evoked activity in distant projection targets. Evoked corticocortical postsynaptic potentials recovered next, within ∼5 min. Spontaneous ECoG and evoked thalamocortical postsynaptic potentials recovered together, after ∼10–15 min. The duration of ECoG depression was shortened 20% by systemic (10 mg/kg) or focal (30 µM) administration of A1R competitive antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). ECoG depression was also shortened by focal application of exogenous adenosine deaminase (ADA; 100 U/mL), and conversely, was prolonged 50% by the non-competitive ADA inhibitor deoxycoformycin (DCF; 100 µM). We concluded that while initial depolarization block is brief, adenosine A1R activation, in part, contributes to the persistent secondary phase of Leao’s cortical spreading depression.