Heat-treatable Al alloys containing Al–2.5wt% Cu (Al–Cu) and Al–2.5wt% Cu–0.3wt% Sc (Al–Cu–Sc) with different grain length scales, i.e., average grain size >10μm ( defined coarse grained, CG), 1–2μm (fine grained, FG), and <1μm (ultrafine grained, UFG), were prepared by equal-channel angular pressing (ECAP). The length scale and Sc microalloying effects and their interplay on the precipitation behavior and mechanical properties of the Al–Cu alloys were systematically investigated. In the Al–Cu alloys, intergranular θ-Al2Cu precipitation gradually dominated by sacrificing the intragranular θ′-Al2Cu precipitation with reducing the length scale. Especially in the UFG regime, only intergranular θ-Al2Cu particles were precipitated and intragranular θ′-Al2Cu precipitation was completely disappeared. This led to a remarkable reduction in yield strength and ductility due to insufficient dislocation storage capacity. The minor Sc addition resulted in a microalloying effect in the Al–Cu alloy, which, however, is strongly dependent on the length scale. The smaller is the grain size, the more active is the microalloying effect that promotes the intragranular precipitation while reduces the intergranular precipitation. Correspondingly, compared with their Sc-free counterparts, the yield strength of post-aged CG, FG, and UFG Al–Cu alloys with Sc addition increased by ~36MPa, ~56MPa, and ~150MPa, simultaneously in tensile elongation by ~20%, ~30%, and 280%, respectively. The grain size-induced evolutions in vacancy concentration/distribution and number density of vacancy-solute/solute–solute clusters and their influences on precipitation nucleation and kinetics have been comprehensively considered to rationalize the length scale-dependent Sc microalloying mechanisms using positron annihilation lifetime spectrum and three dimension atom probe. The increase in ductility was analyzed in the light of Sc microalloying effect and the strength contributions by different strengthening mechanisms was quantified as well.