The cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) is associated with multiple signaling pathways. The signaling pathways leading to epilepsy have been extensively studied and include the Ca²⁺/CaMKiV/CREB pathway, the MAPK/CREB pathway, and the PI3K/Akt/CREB pathway. The regulation of transcription in cells requires CREB phosphorylation and dephosphorylation. Based on a review of the relevant literature, we found that increasing evidence demonstrates that drug-resistant epilepsy might be closely related to the upregulation and phosphorylation of CREB. Previous studies have shown that the mechanisms of epileptogenesis are associated with the over-excitability and sudden synchronous discharge of neurons. In turn, we have learned that inflammation produces proinflammatory factors that damage the blood–brain barrier and activate microglia (MG) and astrocytes (AS). Activated MG and AS not only play neuroprotective roles, but also cause neuroinflammation, which in turn damages nerve cells through CREB-related signaling pathways, leading to reduced effectiveness of antiepileptic drugs and, ultimately, to drug resistance in patients with epilepsy. Therefore, we hypothesized that the formation of drug-resistant epilepsy is related to the regulation of CREB activation or phosphorylation in glial cells activated by chronic inflammation.