Background: Epilepsy is a prevalent neurological illness, impacting about 70 million individuals around the world. Although a large number of patients are controlled with anti-seizure drugs (ASDs), 30%–40% of patients fail to be controlled and develop drugresistant epilepsy (DRE). Objectives: This study aimed to identify miRNa-223 expression and serum level of high mobility group box 1 (HMGB1) as biomarkers for detecting DRE. Methodology: This case-control study comprised 96 subjects categorized to three groups: group I: 46 patients with genetically presumed epilepsy who having DRE; group II: 25 patients with medically controlled genetically presumed epilepsy and group III: 25 healthy individuals. MiRNA-223 expression level was measured by real-time PCR and serum HMGB1 was estimated by ELISA technique. Results: MiRNA-223 expression serum HMGB1 and hs-CRP levels in epilepsy patients were considerably greater than in patients with controlled epilepsy and in healthy controls (p<0.001 for all). The predictive ability of miRNA, HMGB1 and hs-CRP for the detection of epilepsy and DRE using the ROC curve analysis revealed good sensitivities and specificities. Conclusion: MiRNA-223 expression and serum HMGB1 and hs-CRP levels are important biomarkers for diagnosis of epilepsy in suspicious cases. They are also significant for predicting DRE which may pave the way to the development of new antiepileptogenic drugs.