Generally, BCC-based high-entropy alloys containing L21-type precipitates show outstanding creep resistance at high temperatures. However, their weak grain boundary cohesion results in poor room-temperature ductility and limits their industrial applications. This study achieves room-temperature ductility in L21-strengthened Al10Cr13.3Fe59.5Ni11.2Ti4Mo2 alloy through grain substructure refinement with a suitable thermomechanical treatment. We found that the fine and homogeneously distributed L21 precipitates act as effective pinning sites for dislocation movement during hot-rolling, thereby forming a subgrain structure that is three orders of magnitude smaller than that of homogenized alloys. Further, short-term annealing after rolling relieves the internal strain energy by transforming the subgrain boundary structure with energetically favorable dislocation arrangement. Consequently, the L21-strengthened alloy with a refined substructure exhibits a greatly increased plastic strain (∼6%) owing to the reduced microcrack length, and detoured crack propagation around precipitates.