A library of 100 click-chemistry-derived oximes was evaluated as reactivators of butyrylcholinesterase (BChE) inhibited by the nerve agents (NAs) sarin, cyclosarin, VX, and tabun. While reactivation efficiency was highly dependent on the structure of both the NA and the oxime, for each NA-BChE conjugate, we identified reactivators more effective than currently approved oximes for NA poisoning. Detailed kinetic analysis indicated that this enhancement results from both improved molecular recognition-specifically, enhanced binding affinity of the phosphylated conjugates for the oximes-and increased maximal reactivation rates. Molecular modeling of oximes in a near-attack conformation within inhibited BChE revealed critical interactions for productive reactivation. Among all tested oximes, 5B [1-hexyl-2-((hydroxyimino)methyl)pyridinium chloride] emerged as a particularly efficient reactivator for BChE phosphorylated with cyclosarin, with the highest observed overall reactivation rate of 34,120 M