BACKGROUND: The ketogenic diet (KD) is an effective alternative therapy for drug-resistant epilepsy (DRE). However, there are no established predictors for KD effectiveness. We aimed to investigate the impact of 12 months of KD therapy (KDT) on brain connectivity, as measured by functional magnetic resonance imaging (fMRI), and its correlation with seizure control, behavioral/mood alterations, and parental stress. METHODS: Children with DRE were enrolled in this single-center, prospective cohort study from February 2020 to October 2021. They were divided into a control group and a KDT group. The Child Behavior Checklist (CBCL) and Parental Stress Index (PSI) were administered to parents at the initiation of KDT (T0) and at 12 months (T1). Resting-state fMRI was performed at T0 and at 6 months of KDT. The primary outcome was the between-group difference in the change of CBCL/PSI scores, and brain connectivity metrics after KDT, and the secondary outcome involved measuring their correlation with seizure reduction rates. RESULTS: Twenty-two patients with DRE were enrolled. We had 13 patients in the control group and 9 in the KDT group. Our data revealed that 12 months of KDT can reduce monthly seizure frequency. Several subscales of CBCL T-scores were higher at T0 compared with the control group, then becoming comparable at T1. The PSI scores from 'mothers' reports reduced after receiving KDT. The changes in node assortativity (ΔAssortativity) were positively correlated with behavioral problems and negatively with seizure reduction rates in the KD group. CONCLUSIONS: Twelve months of KDT can reduce monthly seizure frequency and improve mood/behavioral disturbances in patients with DRE. Furthermore, KDT could relieve primary caregivers' stress. A lower ΔAssortativity value was associated with better behavioral outcomes and greater seizure reduction. The ΔAssortativity value in fMRI may be a crucial predictor for the effectiveness of KDT.