The neocortex generates short epochs of persistent activity called Up states, which are associated with changes in cellular and network excitability. Using somatosensory thalamocortical slices, we studied the impact of persistent cortical activity during spontaneous Up states on intrinsic cellular excitability (input resistance) and on excitatory synaptic inputs of cortical cells. At the intrinsic excitability level, we found that the expected decrease in input resistance (high conductance) resulting from synaptic barrages during Up states is counteracted by an increase in input resistance due to depolarization per se. The result is a variable but on average relatively small reduction in input resistance during Up states. At the synaptic level, Up states enhanced a late synaptic component of short-latency thalamocortical field potential responses but suppressed intracortical field potential responses. The thalamocortical enhancement did not reflect an increase in synaptic strength, as determined by measuring the evoked postsynaptic current, but instead an increase in evoked action potential (spike) probability due to depolarization during Up states. In contrast, the intracortical suppression was associated with a reduction in synaptic strength, apparently driven by increased presynaptic intracortical activity during up states. In addition, intracortical suppression also reflected a reduction in evoked spike latency caused by depolarization and the abolishment of longer latency spikes caused by stronger inhibitory drive during Up states. In conclusion, depolarization during Up states increases the success of excitatory synaptic inputs to reach firing. However, activity-dependent synaptic depression caused by increased presynaptic firing during Up states and the enhancement of evoked inhibitory drive caused by depolarization suppress excitatory intracortical synaptic inputs.