Series of benzotriazole derivatives were synthesized and evaluated for their Sodium hydrogen exchanger-1 inhibitory potential. All compounds inhibit Sodium hydrogen exchanger-1 in the in-vitro platelet swelling assay. This is perhaps the first report of NHE-1 inhibitory activity of benzotriazole. The 1-alkyl benzotriazole derivatives were found to be more active than the 2-alkyl isomers. The activity increases with increase in chain length of alkyl moiety. Potency increased from that of benzotriazole (IC50 = 192.68 μM) to heptyl derivative (compound 13; IC50 = 59.23 μM). Introduction of electronegative oxygen atom further increased potency as shown by the benzoyl (compound 16, IC50 = 51.57 μM) and sulfonyl groups (compound 17, IC50 = 50.89 μM; compound 18, IC50 = 49.95 μM).