Neurological injury is the major clinical challenge for patients hospitalized after cardiac arrest (CA). CA produces an early systemic inflammatory response associated with significant neurological injury and mortality, but this immune response is poorly defined. We determined the immunological network induced by clinical CA at single-cell resolution. We found that as early as 6h post-arrest, innate immune cell states diverged between patients that went on to have good or poor neurological outcomes. Anti-inflammatory Nectin-2+ monocyte and pro-inflammatory Tim-3+ natural killer (NK) cell states associated with poor outcomes after CA. Cross-talk between these cell states was mediated by cytokines (IFNγ, IL-10) and immune checkpoint receptors (Nectin-2,TIGIT). Ex vivo studies on peripheral blood mononuclear cells from CA patients demonstrated that Nectin-2 expressed by monocytes is a brake on production of IFNγ by NK cells. These findings suggest that immune checkpoints are a compensatory mechanism to ameliorate inflammation and neurological injury after CA. The initial hours after CA may represent a key window for therapeutic intervention in immune checkpoint and inflammatory cytokine axes.