There are at least 11 mitogen‐activated protein kinase (MAPK) phosphatases (MKPs) and only 3 major groups of MAPKs, raising the question of whether these phosphatases have non‐redundant functions in vivo. Using a modified mouse model of local Shwartzman reaction, we found that deletion of the MKP5 gene, but not the MKP1 gene, led to robust and accelerated vascular inflammatory responses to a single dose of LPS injection. Depletion of neutrophils significantly reduced the vascular injury in Mkp5^−/− mice, whereas adoptive transfer of Mkp5^−/− neutrophils replicated the LPS‐induced skin lesions in wild‐type recipients. Neutrophils isolated from Mkp5^−/− mice exhibited augmented p38 MAPK activation and increased superoxide generation on activation. The p38 MAPK inhibitor, SB203580, significantly reduced p47^phox phosphorylation and diminished superoxide production in neutrophils. p38 MAPK phosphorylated mouse p47^phox, and deletion of the p47^phox gene ablated the LPS‐induced vascular injury in Mkp5^−/− mice. Collectively, these results show an earlier unrecognized and non‐redundant function of MKP5 in restraining p38 MAPK‐mediated neutrophil oxidant production, thereby preventing LPS‐induced vascular injury.