Starting with the published 2.0 Å X-ray crystal structure of the transthyretin.(flufenamic acid)2 complex, a simple structure-based ligand design strategy was employed to conceive of N-phenyl phenoxazine transthyretin (TTR) amyloid fibril inhibitors. Fifteen N-phenyl phenoxazines were chemically synthesized and evaluated using a quantitative amyloid fibril assay in vitro. The structure of one of the two most active phenoxazines, 4, bound to TTR was solved to a resolution of 1.9 Å to understand the structural basis of its efficacy. N-phenyl phenoxazine 4 binds similar to the orientation anticipated, although not as deeply into the channel as expected. Like flufenamic acid, 4 mediates binding-induced conformational changes that enable intersubunit H-bonding in tetrameric TTR which may be important for preventing fibril formation. Analytical ultracentrifugation analysis demonstrates that 4 blocks the first step of TTR amyloid fibril formation, that is, tetramer dissociation to the alternatively folded amyloidogenic monomer. Isothermal titration calorimetry was used to determine the binding constants of 4 to TTR and to dissect the enthalpy and entropy contributions associated with ligand binding. Phenoxazine 4 exhibits binding and inhibitor efficacy against WT TTR that is very similar to that of flufenamic acid, unlike the situation with the inhibition of L55P fibril formation where 4 is superior to Flu as an inhibitor but not as a binder. It is clear that 4 functions in part by stabilizing the normally folded tetramer through formation of the TTR·(4)2 complex, which in turn increases the activation energy for tetramer dissociation. The data also suggest that 4 destabilizes the transition state associated with TTR dissociation to the monomeric amyloidogenic intermediate. Future biophysical studies, including kinetic measurements, are needed to understand the exact mechanism(s) of the action of 4.