Cathelicidins are mammalian defense peptides with direct antimicrobial activity and the potential to exert other immunomodulatory effects during the innate immune response. One such function of human cathelicidin is direct binding and inhibition of bacterially derived lipopolysaccharide (LPS), a ligand of toll‐like receptor 4 (TLR4) . Here, we show that physiological concentrations of exogenous murine cathelicidin blunt activation of p38 and ERK mitogen‐activated protein kinases (MAPKs) and decrease tumor necrosis factor‐α (TNFα) release in murine macrophages exposed to LPS, but also other TLR agonists such as lipoteichoic acid and flagellin. In this context, CRAMP is capable of aborting MyD88 synthesis and MyD88/IRAK (interleukin‐1 receptor‐associated kinase)‐4 association in the stimulated macrophages. Exogenous CRAMP can reverse diminished MAPK activation associated with LPS tolerance. By analyzing macrophages from CRAMP^−/− mice, we find their endogenous production of cathelicidin does not inhibit LPS MAPK and cytokine activation, rather CRAMP^−/− cells show slightly diminished responses. CRAMP deficiency does not render mice more susceptible to lethal LPS challenge. These studies indicate the immunomodulatory effects of cathelicidin on macrophage TLR response may vary both on the exogenous vs endogenous origin of peptide and the prior activation state of the cell.