Slip during large earthquakes occurs along faults that are hundreds of kilometers long, yet the dynamic weakening that drives these earthquakes is controlled by nano- to micro-scale frictional processes. We analyzed these processes along experimental faults that slipped at rates approaching seismic velocity, and which displayed intense dynamic weakening of 50%–70%. Sheared fault surfaces were extracted, and then atomic force microscopy was used to (1) measure friction on a sub-micron scale, and (2) determine the three-dimensional morphology at the nano- to micro-scale. The sheared surfaces developed a prevalent anisotropy with a weaker and smoother axis along the slip direction. The nanoscale friction coefficient correlates well with sheared-surface roughness: the friction coefficients dropped only on surfaces with root mean square (RMS) values of <100 nm, while rougher surfaces showed no weakening. Our analysis indicates that slip smoothing at high slip velocities can be an effective mechanism of dynamic weakening.