Currently the 5-year survival rate for osteosarcoma patients with pulmonary metastasis is less than 30%, identifying a need for novel approaches to inhibit metastasis. Consistent with an emerging understanding of the cancer-inflammation relationship, a requirement for neutrophils in metastasis was recently proposed. Here we assessed the potential requisite of neutrophils and the effects of two novel anti-inflammatory agents in osteosarcoma metastasis: LT-peptide and GML (GM1-Targeted Linoleate-Containing TLR2 Ligand). Using an osteosarcoma lung metastatic mouse model, we found increased neutrophil levels in the lungs in the presence of osteosarcoma cells and reduced metastatic burden following antibody-mediated neutrophil depletion or GML treatment. These preclinical studies identify targeting neutrophils as a novel therapeutic paradigm in osteosarcoma metastasis and contribute to our understanding of the mechanisms involved in metastatic osteosarcoma, thus supporting the development of anti-inflammatory therapies as a promising approach to improve the outcomes of osteosarcoma patients.