Organophosphate poisoning can occur from exposure to agricultural pesticides or chemical weapons. This exposure inhibits acetylcholinesterase resulting in increased acetylcholine levels within the synaptic cleft causing loss of muscle control, seizures, and death. Mitigating the effects of organophosphates in our bodies is critical and yet an unsolved challenge. Weaponized organophosphates are a deadly threat to armed forces and civilians (e.g., exposure to one droplet of VX exceeds the LD50 of ~15 μg/kg). Here, we present two computational strategies to 1) identify a novel protein acting as a stoichiometric bioscavenger to covalently bind organophosphates, and 2) improve the stability and activity of organophosphate hydrolase as a catalytic bioscavenger through allosteric modulation. We use our first computational strategy, integrating structure mining and modeling approaches, to identify novel candidates capable of interacting with a serine hydrolase probe (either covalently or with equilibrium binding constants ranging from 20 to 120 µM). One candidate Smu. 1393c catalyzes the hydrolysis of the organophosphate omethoate (kcat/Km of (2.0±1.3)×10-1 M-1s-1) and paraoxon (kcat/Km of (4.6±0.8)×103 M-1s-1), V- and G-agent analogs respectively. In addition, Smu. 1393c protects acetylcholinesterase activity from being inhibited by two organophosphate simulants. We demonstrate that the utilized approach is an efficient and highly-extendable framework for the development of prophylactic therapeutics against organophosphate poisoning. Organophosphate hydrolase (OPH) degrades many classes of organophosphates and plays an important role in organophosphate remediation. Here, we demonstrate our second computational strategy of protein design to enhance OPH’s enzymatic hydrolysis of organophosphates and test on paraoxon, a G-agent analog, and omethoate, a V-agent analog. We identify five hotspot residues for allosteric regulation and assay these mutants for hydrolysis activity against paraoxon. A number of the predicted mutants exhibit enhanced paraoxon activity over wild type OPH (kcat =907 s-1), such as T54I/T199I (1260 s-1) while the Km remains relatively unchanged. Computational protein dynamics study reveals four distinct distal regions that display significant changes in conformation dynamics. The enzymatic enhancement of OPH validates a computational design method that is both efficient and readily adapted as a general procedure for enzymatic enhancement.