Fundamental processes of the seismic cycle in subduction zones, including those controlling the recurrence and size of great earthquakes, are still poorly understood. Here, by studying the 2016 earthquake in southern Chile - the first large event within the rupture zone of the 1960 earthquake (moment magnitude (M _w) = 9.5) - we show that the frictional zonation of the plate interface fault at depth mechanically controls the timing of more frequent, moderate-size deep events (M _w < 8) and less frequent, tsunamigenic great shallow earthquakes (M _w > 8.5). We model the evolution of stress build-up for a seismogenic zone with heterogeneous friction to examine the link between the 2016 and 1960 earthquakes. Our results suggest that the deeper segments of the seismogenic megathrust are weaker and interseismically loaded by a more strongly coupled, shallower asperity. Deeper segments fail earlier (~60 yr recurrence), producing moderate-size events that precede the failure of the shallower region, which fails in a great earthquake (recurrence >110 yr). We interpret the contrasting frictional strength and lag time between deeper and shallower earthquakes to be controlled by variations in pore fluid pressure. Our integrated analysis strengthens understanding of the mechanics and timing of great megathrust earthquakes, and therefore could aid in the seismic hazard assessment of other subduction zones.