This work examines the effect of environmental humidity on rate-and-state friction behavior of nanoscale silica-silica nanoscale contacts in an atomic force microscope, particularly, its effect on frictional ageing and velocity-weakening vs. strengthening friction from 10 nm/s to 100 μm/s sliding velocities. At extremely low humidities (\(\ll 1\% RH\)), ageing is nearly absent for up to 100 s of nominally stationary contact, and friction is strongly velocity-strengthening. This is consistent with dry interfacial friction, where thermal excitations help overcome static friction at low sliding velocities. At higher humidity levels (10–40% RH), ageing becomes pronounced and is accompanied by much higher kinetic friction and velocity-weakening behavior. This is attributed to water-catalyzed interfacial Si–O-Si bond formation. At the highest humidities examined (> 40% RH), ageing subsides, kinetic friction drops to low levels, and friction is velocity-strengthening again. These responses are attributed to intercalated water separating the interfaces, which precludes interfacial bonding. The trends in velocity-dependent friction are reproduced and explained using a computational multi-bond model. Our model explicitly simulates bond formation and bond-breaking, and the passivation and reactivation of reaction sites across the interface during sliding, where the activation energies for interfacial chemical reactions are dependent on humidity. These results provide potential insights into nanoscale mechanisms that may contribute to the humidity dependence observed in prior macroscale rock friction studies. They also provide a possible microphysical foundation to understand the role of water in interfacial systems with water-catalyzed bonding reactions, and demonstrate a profound change in the interfacial physics near and above saturated humidity conditions.