The use of alkaline activator in alkali-activated materials (AAMs) may pose risk of alkali-silica reaction (ASR), and the variations in the mixture design could have great influence on the performance of AAMs system. In this case, this paper investigated the effects of slag fineness (3000–8000 cm²/g) and water-to-binder (w/b) ratio (0.5–0.8) on ASR behavior of alkali-activated slag (AAS) mortars under accelerated mortar testing conditions as specified in ASTM C1260. The length change, mass gain, microstructure and formation of ASR products were examined to evaluate the degradation caused by ASR. It was found for the first time that slag fineness induces a “pessimum effect” in the ASR expansion of AAS mortars. On the other hand, there is a “pessimum effect” in the influence of w/b ratio on ASR expansion in the early-stage (≤14d), and the induced expansion increased with an increase in w/b ratio in the late-stage (>14d). The mechanism governing the effect of slag fineness and w/b ratio is complicated and cannot be explained solely by the properties of ASR products. This work contributes to the understanding of ASR in AAMs system and could provide a basis for the mixture optimization of AAMs.