The relationship between humidity and water content in a hydrating cement paste is largely controlled by the nanostructure of the C–S–H gel. Current hydration models do not describe this nanostructure, thus sorption isotherms and self-desiccation are given as constitutive inputs instead of being predicted from microstructural evolution. To address this limitation, this work combines a C–S–H gel description from nanoscale simulations with evolving capillary pore size distributions from a simple hydration model. Results show that a progressive densification of the C–S–H gel must be considered in order to explain the self-desiccation of low-alkali pastes. The impact of C–S–H densification on the evolution of microstructure and sorption isotherms is then discussed, including the effect of water-to-cement ratio, cement powder fineness, and curing temperature. Overall, this work identifies an area where nanoscale simulations can integrate larger-scale models of cement hydration and poromechanics.