Sulindac (SLD) exhibits both the highest inhibitory activity towards human aldose reductase (AR) among popular non‐steroidal anti‐inflammatory drugs and clear beneficial clinical effects on Type 2 diabetes. However, the molecular basis for these properties is unclear. Here, we report that SLD and its pharmacologically active/inactive metabolites, SLD sulfide and SLD sulfone, are equally effective as un‐competitive inhibitors of AR in vitro. Crystallographic analysis reveals that π–π stacking favored by the distinct scaffold of SLDs is pivotal to their high AR inhibitory activities. These results also suggest that SLD sulfone could be a potent lead compound for AR inhibition in vivo.