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The collision between the Indian and Eurasian plates drives tectonic uplift and evolving landscapes over geological time scales. Much of this evolution is accommodated by seismic processes. However, the relationship between long-term geological processes and short-term seismic cycles is challenging to unravel because of their disparate spatial and temporal scales. Here, we investigate the impact of the internal dynamics of the orogenic wedge on the cycle of Himalayan earthquakes, linking structural models with seismic cycle simulations to show how earthquake patterns may have changed over time. Balanced cross-sections with fault-bend folding at different stages of structural evolution show that frontal thrusts in the Himalayas accumulate slip at different rates across the wedge and over time, depending on the architectural layout of the thrust sheet. Along-strike variations in structural evolution along the Himalayan front may lead to lateral and down-dip segmentation of long-term slip rate, affecting the magnitude and recurrence patterns of earthquakes. Spatio-temporal earthquake patterns may shift every ∼0.3-1.3 Myr as the hanging wall evolves, with implications for seismic hazards in the Nepal Himalayas.