Background: This study aimed to identify metabolic parameters at different time points of ketogenic diet therapy (KDT) and investigate their association with response to KDT in pediatric drug-resistant epilepsy (DRE). Methods: Prospectively, twenty-nine patients (0.67~20 years old) with DRE received classic ketogenic diet with non-fasting, gradual KD initiation protocol (GRAD-KD) for 1 year were enrolled. A total of 22 patients remaining in study received blood examinations at baseline, 3rd, 6th, 9th, and 12th months of KDT. β-hydroxybutyrate, free carnitine, acylcarnitines, and amino acids were compared between responders (seizure reduction rate ≥ 50%) and non-responders (seizure reduction rate < 50%) to identify the effectiveness of KDT. Results: The 12-month retention rate was 76%. The responders after 12 months of KDT were 59% (13/22). The free carnitine level decreased significantly at 9th months (p < 0.001) but increased toward baseline without symptoms. Propionyl carnitine (C3), Isovaleryl carnitine (C5), 3-Hydroxyisovalerylcarnitine (C5:OH) and methylmalonyl carnitine (C4-DC) decreased but 3-hydroxybutyrylcarnitine (C4:OH) increased significantly at 12th months of KDT. The glycine level was persistently higher than baseline after KDT. KDT responders had lower baseline C3 and long-chain acylcarnitines, C14 and C18, as well as lower C5, C18, and leucine/isoleucine. Conclusions: KDT should be avoided in patients with non-ketotic hyperglycemia. Routine carnitine supplementation is not recommended because hypocarnitinemia was transient and asymptomatic during KDT. Better mitochondrial βoxidation function associates with greater KDT response.