Significance Toxin–antitoxin systems are enigmatic and diverse elements of bacterial and bacteriophage genomes. We have uncovered remarkable versatility in an antitoxin protein domain that has evolved to neutralize dozens of different toxin domains. We find that antitoxins carrying this domain—Panacea—form complexes with their cognate toxins, indicating a direct neutralization mechanism, and that Panacea can be evolved to neutralize a noncognate and nonhomologous toxin with just two amino acid substitutions. This raises the possibility that this domain could be an adaptable universal or semi-universal protein neutralizer with significant biotechnological and medical potential.