This study explored the time-varying alkali-activation effects of the lightweight aggregates (LWA) on the interfacial transition zone (ITZ) of the alkali-activated slag concrete with different curing ages, molar ratios, and alkali concentrations from 28 to 300 d. The improved micromechanical performance of the ITZ at 28 d stemmed from the early-age internal curing effect of the porous LWA. However, the post-28 d internal curing effect diminished, with the alkali-activation dominating the performance of the ITZ from 28 to 300 d. Although alkali-activated cement possessed early strength characteristics, the deconvolved phase results illustrated that alkali activation persisted in the ITZ between the LWA and cement from 28 to 300 d, leading to a high proportion of calcium silica aluminate hydrate. As a marker, Fe from the lightweight iron-rich aggregates mitigated into the alkali-activated cement, demonstrating the alkali-activated reaction between the LWA and alkali-activated slag matrix. Molecular dynamics simulations further characterized that the low content of Fe did not decrease the overall strength of the ITZ. The interfacial interaction energy revealed the alkali-activation between the LWA and cement compensated for the weakening of mechanical properties caused by Fe ions on the ITZ.