Discovery of glycan‐competitive galectin‐3‐binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin‐3 accumulation at damaged vesicles, hence revealing galectin‐3–glycan interactions involved in fibrosis progression and in intracellular galectin‐3 activities, is reported. 3,3′‐Bis‐(4‐aryltriazol‐1‐yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin‐1, ‐2, ‐3, and ‐4 N‐terminal, ‐4 C‐terminal, ‐7 and ‐8 N‐terminal, ‐9 N‐terminal, and ‐9 C‐terminal domains. Compounds displaying low‐nanomolar affinities for galectins‐1 and ‐3 were identified in a competitive fluorescence anisotropy assay. X‐ray structural analysis of selected compounds in complex with galectin‐3, together with galectin‐3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin‐3. The most potent galectin‐3 antagonist was demonstrated to act in an assay monitoring galectin‐3 accumulation upon amitriptyline‐induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin–carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin‐induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone. Dot removal: Highly potent galectin‐1 and ‐3 antagonists were discovered through synthesis, optimization, and structural analysis of doubly C3‐aryltriazolyl‐substituted thiodigalactosides. The synthetic ligands efficiently inhibit intracellular galectin‐3 accumulation in dots on damaged vesicles and attenuate experimentally induced lung fibrosis.