Acetylcholinesterase is vital for normal operation of many processes in the body. Following exposure to organophosphorus (OP) nerve agents, death can ensue without immediate medical intervention. Current therapies mitigate the cholinergic crisis caused by nerve agents but do not fully prevent long‐term health concerns, for example, brain damage following seizures. Human butyrylcholinesterase (HuBChE) is a stoichiometric bioscavenger being investigated as an antidote for OP nerve agent poisoning. HuBChE sequesters OP nerve agent in the bloodstream preventing the nerve agent from reaching critical target organ systems. HuBChE was effective when used as both a pre‐treatment and as a post‐exposure therapy. HuBChE has potential for use in both military settings and to protect civilian first responders in situations where nerve agent usage is suspected. We reviewed various animal models studies evaluating the efficacy of HuBChE against nerve agent exposure, pursuant to its submission for approval under the FDA Animal Rule.