TLR4‐mediated pathways are central to several human diseases, such as sepsis and pathogen infection. Pharmacological down‐regulation of bacterially‐activated TLR4 signaling provides a potential way to treat sepsis. Also, TLR4 activation by invading pathogens triggers innate immunity. We have previously shown that lysophosphatidylcholine (LPC) is a potent modulator of innate immunity through suppression of LPS‐induced nitric oxide (NO) production. LPC is a true ligand of Toll‐like receptors (TLR) 2/1 and 4 induces a pro‐inflammatory phenotype in the absence of LPS. Macrophages are central to mount the immune response and display two different phenotypes, M1 and M2, which represent different ends of functional states of cell polarization. Here, we show that LPC counteracts the proinflammatory phenotype M1. Instead it induces the morphology of the M2 phenotype as demonstrated by both electron and optical microscopy. Cells simultaneously exposed to LPS and LPC display a downregulation of inducible nitric oxide synthase and express high levels of arginase. Such effects are largely associated to the modulation of actin cytoskeleton and are induced upon LPC‐mediated activation of protein kinase C zeta. Thus, in the presence of LPC and LPS macrophages display an anti‐inflammatory phenotype that is critical for the resolution of inflammation. In conclusion, detailing of signaling pathways triggered by lysophospholipids in immune cells may ultimately lead to novel modulators of innate immunity and disease therapies.