<p>Saxitoxin (STX) is among the most potent toxins known, is classified as a chemical weapon, and is the archetype of the paralytic shellfish toxin (PST) family produced by marine and freshwater harmful algal blooms (HAB). STX causes paralysis and death through inhibition of voltage-gated sodium channels (Na_Vs), has no antidote, and poses a public health and commercial fishing threat due to its accumulation in seafood and increasing HAB occurrences. Although STX is lethal to varied vertebrates, including humans, certain frogs resist STX poisoning. This phenotype is thought to depend on soluble toxin sponge high-affinity STX binding proteins (saxiphilins, Sxphs) that provide resistance through a competition mechanism different from classic target site ion channel mutation mechanisms. Here, we test this idea and show that a single dose of American bullfrog (<i>Rana catesbeiana</i>) Sxph (<i>Rc</i>Sxph) is sufficient to counteract STX neurotoxicity and lethality in female mice using paradigms where STX and Sxph are administered together or sequentially in either order. Importantly, this function requires the <i>Rc</i>Sxph high-affinity STX binding site. Our findings provide in vivo validation that Sxphs are toxin sponges that protect against STX poisoning and highlight the potential to harness this protein class as antidotes for PSTs and other toxins.</p>