NMR spectroscopy and ITC are powerful methods to investigate ligand-protein interactions. Here, we present a versatile and sensitive fluorine NMR approach that exploits the 19F nucleus of 19F labeled carbohydrates as a sensor to study glycan binding to lectins. Our approach is illustrated with the 11 kDa Cyanovirin-N, a mannose binding anti-HIV lectin. Two fluoro-deoxy sugar derivatives, methyl 2-deoxy-2-fluoro-α-D-mannopyranosyl-(1→2)-α-D-mannopyranoside and methyl 2-deoxy-2-fluoro-α-D-mannopyranosyl-(1→2)-α-D-mannopyranosyl-(1→2)-α-D-mannopyranoside were utilized. Binding was studied by 19F-NMR spectroscopy of the ligand and 1H-15N HSQC NMR spectroscopy of the protein. The NMR data agree well with those obtained from the equivalent reciprocal and direct ITC titrations. Our study shows that strategic design of fluorinated ligands and fluorine NMR spectroscopy for ligand screening holds great promise for easy and fast identification of glycan binding as well as for their use in reporting structural and/or electronic perturbations that ensue upon interaction with a cognate lectin.