A combined computational and experimental study has been carried out to explore and test a quantitative correlation relationship between the relative catalytic efficiency (RCE) of human butyrylcholinesrase (BChE) mutant-catalyzed hydrolysis of substrate (-)-cocaine and the total hydrogen bonding energy (tHBE) of the carbonyl oxygen of the substrate with the oxyanion hole of the enzyme in the modeled transition-state structure (TS1), demonstrating a satisfactory linear correlation relationship between ln(RCE) and tHBE. The satisfactory correlation relationship has led us to computationally predict and experimentally confirm new human BChE mutants that have a further improved catalytic activity against (-)-cocaine, including the most active one (the A199S/F227S/S287G/A328W/Y332G mutant) with a 2790-fold improved catalytic efficiency (kcat/KM = 2.5 × 109 min-1 M-1) compared to the wild-type human BChE. Compared to the reference mutant (the A199S/S287G/A328W/Y332G mutant) tested in the reported clinical development of an enzyme therapy for cocaine dependence treatment, this new mutant (with a newly predicted additional F227S mutation) has an improved catalytic efficiency against (-)-cocaine by ∼2.6-fold. The good agreement between the computational and experimental ln(RCE) values suggests that the obtained correlation relationship is robust for computational prediction. A similar correlation relationship could also be explored in studying BChE or other serine hydrolases/esterases with an oxyanion hole stabilizing the carbonyl oxygen in the rate-determining reaction step of the enzymatic hydrolysis of other substrates.