Ribonuclease inhibitors, both synthetic and natural have been intensively sought after for various therapeutic purposes. Angiogenin, a potent inducer of angiogenesis belongs to the ribonuclease superfamily. Angiogenin has a similar arrangement of ribonucleolytic site residues as ribonuclease A (RNase A), a model protein of this superfamily. In this study, we have investigated the potential of 3´-O-carboxy esters of thymidine, green tea polyphenols and their copper complexes to inhibit RNase A and angiogenin. Agarose gel based assays and precipitation assays showed inhibition of RNase A, which was further confirmed by inhibition kinetics. The 3´-O-carboxy esters of thymidine behave as competitive inhibitors whereas green tea polyphenols and their copper complexes show noncompetitive inhibition with micromolar inhibition constants. It was observed that the polyphenols with a gallate moiety were better inhibitors of RNase A. Modified nucleosides also inhibited the ribonucleolytic activity of angiogenin and suppressed angiogenin-induced angiogenesis. Though the green tea polyphenols and their copper complexes do not affect the ribonucleolytic activity of angiogenin to a large extent, they inhibit angiogenin-induced angiogenesis. Docking studies substantiate the nature of inhibition for RNase A and angiogenin by these inhibitors. Our next study concentrates on the ability of human serum albumin (HSA), the most abundant carrier protein, to bind these inhibitors. The compounds bind to HSA with association constants of the order of 104 M-1. These compounds occupy site 1 of HSA resulting in the quenching of fluorescence of the sole Trp in HSA, Trp 214. The inefficiency of the nongallate containing polyphenol to quench the fluorescence of HSA emphasizes the role of the gallate moiety in the interaction process. The close proximity of Trp 214 to the ligands resulted in efficient energy transfer from the protein to the ligands. Docking results corroborate the experimental studies and point to the same site of interaction of the molecules with HSA. Thermodynamic analyses suggested that an initial hydrophobic association is followed by van der Waals interactions and hydrogen bonding on complexation.