Tristetraprolin (TTP) is an acute phase protein, and its expression is rapidly up‐regulated by inflammatory signals, such as lipopolysaccharide (LPS) and cytokines. TTP regulates gene expression by governing the mRNA stability of its target genes, which include cytokines and growth factors. MAP kinase phosphatase‐1 (MKP‐1) is a nuclear phosphatase that inhibits p38 mitogen‐activated protein kinase (MAPK) signaling. This study investigated the role of MKP‐1 in TTP expression in A549 human lung epithelial cells, THP‐1 human macrophages, J774 mouse macrophages, and primary mouse macrophages. TTP and MKP‐1 expression was increased by cytokines or LPS. Silencing of MKP‐1 by siRNA enhanced TTP expression in response to LPS, and LPS‐induced TTP expression was increased in macrophages from MKP‐1 (−/−) mice as compared with that in macrophages from wild‐type animals. The inhibition of p38 MAPK by SB202190 reduced TTP expression. In conclusion, MKP‐1 suppressed TTP expression by inhibiting p38 MAPK pathway.