Galectin-3 is a member of a family of β-galactoside-binding proteins. A substantial body of literature reports that galectin-3 plays important roles in cancer, inflammation, and fibrosis. Small-molecule galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent galectin-3 inhibitors. Compounds 36, 40, and 45 were selected for further in vivo evaluation. The synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based galectin-3 inhibitors are described.