Parasite‐derived lipids may play important roles in host‐pathogen interactions and escape mechanisms. Herein, we evaluated the role of schistosomal‐derived lipids in Toll‐like receptor (TLR)-2 and eosinophil activation in Schistosoma mansoni infection. Mice lacking TLR2 exhibited reduced liver eosinophilic granuloma, compared with that of wild‐type animals, following S. mansoni infection. Decreased eosinophil accumulation and eosinophil lipid body (lipid droplet) formation, at least partially due to reduced production of eotaxin, interleukin (IL)‐5, and IL‐13 in S. mansoni-infected TLR2-/- mice, compared with the corresponding production in wild‐type mice, was noted. Although no differences were observed in survival rates during the acute schistosomal infection (up to 50 days), increased survival of TLR2-/- mice, compared with survival of wild‐type mice, was observed during the chronic phase of infection. Schistosomal lipid extract– and schistosomal‐derived lysophosphatidylcholine (lyso‐PC)-stimulated macrophages in vitro induced TLR2‐dependent NF‐kB activation and cytokine production. Furthermore, in vivo schistosomal lyso‐PC administration induced eosinophil recruitment and cytokine production, in a mechanism largely dependent on TLR2. Taken together, our results suggest that schistosomal‐derived lyso‐PC may participate in cytokine production and eosinophil activation through a TLR2‐dependent pathway in S. mansoni infection. Moreover, our results suggest that TLR2‐dependent inflammatory reaction, cytokine production, and eosinophil recruitment and activation may contribute to the pathogenesis and lethality in the chronic phase of infection.