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Valproic acid (VPA) represents one of the most efficient antiepileptic drugs (AEDs) with either general or focal seizures, but a certain percentage of patients are not recovered or even worse, the mechanism under this phenomenon remains unclear. Here, we retrospectively reviewed 16 patients who received awake craniotomy surgery. Intro-operative high density electrocorticogram (ECoG) was used to record the local field potential (LFP) response to VPA treatment. We found the less efficacy of VPA monotherapy was associated with ECoG spectrum power shift from higher to lower frequency after VPA injection, together with increased synchronization of the LFP. Furthermore, we established the computational model to testify the hypothesis that the ineffectivity of VPA may be caused by excitatory dynamic rebound during the inhibitory power increasing. In addition to test the hypothesis, we employed the mice with Kanic Acid (KA)-induced epileptic model to confirm that it would be inhibited by VPA on behavior and neural activity. Also, the neural activity shows significant rebound on spike firing. Then we discovered that the LFP would increase the power spectral density in multiple wave bands after the VPA delivers. These findings suggest that less efficacy of valproic acid monotherapy in focal seizures may be caused by neural excitatory rebound which mediated by elevated inhibitory power.