<p>Epilepsy is a persistent neurological condition that impacts millions of individuals globally. Neuroinflammation is regarded as a key contributor to the process of epileptogenesis. Several preclinical studies investigated the protective role of pentoxifylline (PTX) in an experimental model of epilepsy. This study aimed to investigate the fundamental role of pentoxifylline and its protective pathways in generalized epilepsy patients. In this controlled parallel randomized clinical study, 66 patients with generalized epilepsy were randomly assigned to two groups: group 1 (the control group; <i>n</i> = 33) received 100&#xa0;mg of phenytoin three times daily (t.i.d.) for 6&#xa0;months, while group 2 (the pentoxifylline group; <i>n</i> = 33) received 100&#xa0;mg of phenytoin t.i.d. and 400&#xa0;mg of pentoxifylline twice daily for 6&#xa0;months. Participants were evaluated at baseline and 6&#xa0;months after treatment to assess the serum levels of high mobility group box-1 protein (HMGB-1), toll-like receptor-4 (TLR-4), nuclear factor kappa-B (NF-κB), amyloid beta (Aβ), and nuclear factor erythroid 2–related factor 2 (Nrf2). The clinical outcome was assessed through a mini-mental state examination (MMSE), quality of life questionnaire (QOLIE-31), and seizure frequency. After treatment, the pentoxifylline group demonstrated a significant decrease in serum levels of HMGB1 (<i>P</i> = 0.016), TLR-4 (<i>P</i> = 0.007), NF-κB (<i>P</i> = 0.008), and Aβ (<i>P</i> = 0.012) and a significant increase in serum Nrf2 (<i>P</i> = 0.007). Additionally, the pentoxifylline group showed a significant increase in both the MMSE score (<i>P</i> = 0.001) and QOLIE-31 score (<i>P</i> = 0.001), which was associated with a significant decrease in the frequency of seizures (<i>P</i> = 0.025). Pentoxifylline may be considered a promising adjuvant therapy for generalized epilepsy patients. Trial registration number: NCT05637086, registration date: 27–11-2022.</p>