Taurine/α-ketoglutarate dioxygenase is an important enzyme that takes part in the cysteine catabolism process in the human body and selectively hydroxylates taurine at the C¹-position. Recent computational studies showed that in the gas-phase the C²-H bond of taurine is substantially weaker than the C¹-H bond, yet no evidence exists of 2-hydroxytaurine products. To this end, we performed a detailed computational study on the selectivity patterns in TauD. The calculations show that the second-coordination sphere and the protonation states of residues play a major role in guiding the enzyme to the right selectivity. Specifically, a single proton on an active site histidine residue can change the regioselectivity of the reaction through its electrostatic perturbations in the active site and effectively changes the C¹-H and C²-H bond strengths of taurine. This is further emphasized by many polar and hydrogen bonding interactions of the protein cage in TauD with the substrate and the oxidant that weaken the pro-R C¹-H bond and triggers a chemoselective reaction process. Our large cluster models reproduce the experimental free energy of activation excellently.