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Background: Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. Objective: In search of potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized. Methods: This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out Results: In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety play a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetics studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki). Conclusion: Subsequently, 3e, 3f, 3l and 3p were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 µM, while 3d as a noncompetitive inhibitor of bCA-II (Ki = 2.5±0.015 µM), however, 3g demonstrated competitive inhibition of hCA-II with Ki value of 5.95±0.002 µM. The selectivity index reflects that the compound 3g is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.