A unique low-to-high friction transition is observed during unlubricated sliding in metals with a gradient nano-grained (GNG) surface layer. After persisting in the low-friction state (0.2–0.4) for tens of thousands of cycles, the coefficients of friction in the GNG copper (Cu) and copper-silver (Cu–5Ag) alloy start to increase, eventually reaching a high level (0.6–0.8). By monitoring the worn surface morphology evolution, wear-induced damage accumulation, and worn subsurface structure evolution during sliding, we found that the low-to-high friction transition is strongly correlated with distinct microstructural instabilities induced by vertical plastic deformation and wear-off of the stable nanograins in the subsurface layer. A very low wear loss of the GNG samples was achieved compared with the coarse-grained sample, especially during the low friction stage. Our results suggest that it is possible to postpone the initiation of low-to-high friction transitions and enhance the wear resistance in GNG metals by increasing the GNG structural stability against grain coarsening under high loading.