Author Summary In patients with focal epilepsy, seizures originate in the focus and propagate across the brain. Over years of duration of disease, these repeated seizures lead to network reorganization and disruption. We hypothesized that these changes occur along a framework that could be identified through healthy brain architecture, with the greatest changes occurring closest to the seizure focus and decreasing as distance from the focus increases. In this work we detected this pattern of change in functional and structural networks when distance to the focus was measured by functional and structural connectivity, respectively. Overall, this work presents a framework of spatiotemporal network progression over duration of disease related to the seizure focus and healthy brain architecture that may predict individual network evolution in focal epilepsy. Abstract We measured MRI network progression in mesial temporal lobe epilepsy (mTLE) patients as a function of healthy brain architecture. Resting-state functional MRI and diffusion-weighted MRI were acquired in 40 unilateral mTLE patients and 70 healthy controls. Data were used to construct region-to-region functional connectivity, structural connectivity, and streamline length connectomes per subject. Three models of distance from the presumed seizure focus in the anterior hippocampus in the healthy brain were computed using the average connectome across controls. A fourth model was defined using regions of transmodal (higher cognitive function) to unimodal (perceptual) networks across a published functional gradient in the healthy brain. These models were used to test whether network progression in patients increased when distance from the anterior hippocampus or along a functional gradient in the healthy brain decreases. Results showed that alterations of structural and functional networks in mTLE occur in greater magnitude in regions of the brain closer to the seizure focus based on healthy brain topology, and decrease as distance from the focus increases over duration of disease. Overall, this work provides evidence that changes across the brain in focal epilepsy occur along healthy brain architecture.