CO poisoning results in >50,000 emergency department visits in the United States each year and CO exposure is associated with long-term neurological deficits and death. Although standard oxygen-based therapies are effective, they can be limited either by the rate of CO clearance from the bloodstream or the need to travel to a specialized facility. We and others envision that an antidote capable of selectively sequestering CO can provide an orthogonal means of rapidly treating acute CO poisoning. Taking inspiration from small-molecule models of metalloprotein active sites, we are developing a bulky, water-soluble metalloporphyrin antidote platform. A proof-of-principle Fe(II) complex can bind CO, sequester CO from carboxyhemoglobin, and rescue CO-poisoned red blood cells. Heavier group 8 congeners form more stable complexes with CO, but at the expense of rapid ligand exchange kinetics. Preliminary data highlight the ability of a proof-of-principle Fe(II) complex to increase survival in a mouse model of CO poisoning.