Background <p>Post-surgical epilepsy (PSE) is a common and debilitating complication after brain tumor resection, impairing recovery and quality of life. Serum neurofilament light chain (NfL) and inflammatory cytokines are emerging biomarkers of neuro-axonal injury and neuroinflammation, yet their combined predictive value for PSE remains underexplored.</p> Materials and methods <p>This single-center retrospective diagnostic study enrolled 158 adults undergoing first-time brain tumor resection (2020–2024). Serum levels of NfL, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) were measured preoperatively and on postoperative days 1, 3, and 7. The primary outcome was PSE occurrence within 3 months, diagnosed per International League Against Epilepsy (ILAE) criteria. Independent predictors were identified via multivariable logistic regression, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis.</p> Results <p>Forty-two patients (26.6%) developed PSE. The PSE group exhibited significantly higher serum NfL, IL-6, TNF-α, and CRP levels on postoperative day 3 (all <i>P</i> &lt; 0.01). In multivariable analysis, elevated day-3 NfL (adjusted odds ratio [aOR] = 3.42, 95% confidence interval [CI]: 1.83–6.38) and IL-6 (aOR = 2.75, 95% CI: 1.50–5.05) were independent predictors of PSE. The combination model (NfL + IL-6) demonstrated superior diagnostic accuracy (area under the curve [AUC] = 0.86, 95% CI: 0.80–0.92) compared to single biomarkers.</p> Conclusions <p>The combination of serum NfL and IL-6, measured early after surgery, effectively predicts PSE risk following brain tumor resection. This biomarker panel may facilitate early identification of high-risk patients for targeted monitoring and prophylactic intervention.</p> Clinical trial <p>Not applicable.</p>