Epilepsy is a chronic widely prevalent neurologic disorder, affecting brain functions with a broad spectrum of deleterious consequences. High mobility group box1 (HMGB1) is a nuclear non‐histone protein that targets vital cell receptor of toll‐like receptor 4 (TLR4) and advanced glycation end products (RAGE). HMGB1 mediated TLR4/RAGE cascade has been scored as a key culprit in neuroinflammatory signalling that critically evokes development of impaired cognition and epilepsy. The current study aimed to investigate the neuroprotective effect of pentoxifylline (PTX) on pentylenetetrazol (PTZ)‐kindling rats by its anti‐inflammatory/antioxidant capacity and its impact on memory and cognition were investigated, too. PTZ was intraperitoneally injected 35 mg/kg, every 48 h, for 14 doses, to evoke kindling model. Phenytoin (30 mg/kg, i.p.) and PTX (60 mg/kg, i.p.) or their combination were given once daily for 27 days. PTX treatment showed a statistically significant effect on behavioural, histopathological and neurochemical analysis. PTX protected the PTZ kindling rats from epileptic seizures and improved memory and cognitive impairment through the Morris water maze (MWM) test. Furthermore, PTX reversed PTZ hippocampal neuronal loss by decreasing protein expression of amyloid‐β peptide (Aβ), Tau and β site‐amyloid precursor protein cleavage enzyme 1 (BACE1), associated with a marked reduction in expression of inflammatory mediators such as HMGB1, TL4, and RAGE proteins. Furthermore, PTX inhibited hippocampal apoptotic caspase 1 protein, total reactive oxygen species (TROS) along with upregulated erythroid 2‐related factor 2 (Nrf2) content. In conclusion, PTX or its combination with phenytoin represent a promising drug to inhibit the epilepsy progression via targeting the HMGB1/TLR4/RAGE signalling pathway.