Exosomes are extracellular vesicles that are released into circulation to facilitate communication between cells. These vesicles transport a variety of cargo, including cytokines, bioactive lipids, and regulatory RNA, that can modulate immune function. Immune suppression exhibited by dairy cows during early lactation may involve exosome-mediated communication between immune cells. We sought to determine whether fatty acids that are elevated in circulation of dairy cows during early lactation can alter exosome-mediated inflammatory signaling. Specifically, we studied the ability of bovine exosomes to alter immune responses of primary bovine monocyte-derived macrophages (MDM). Circulating monocytes were isolated from 6 healthy mid-lactation Holstein cows. Cells were incubated for 7–10 d to allow for differentiation into MDM. Cells were treated with either fatty-acid-free bovine serum albumin (BSA; control) or palmitic acid (PA; 100 μM) plus BSA carrier for 6 h before exosomes were isolated from culture media. Untreated MDM were incubated for 12 h with either no treatment or exosomes from PA or BSA treatment, equalized by protein concentration of the isolated exosomes. Cells were then incubated for 6 h with or without LPS (100 ng/mL) before media was harvested for cytokine analysis. Treatment with exosomes from either control or PA-exposed MDM increased TNFα concentrations independently of LPS treatment (P < 0.001 compared with untreated cells), and in fact, PA exosome treatment resulted in greater TNFα concentrations than LPS treatment (P = 0.03). Surprisingly, PA exosomes also attenuated the TNFα response to LPS compared with control exosomes (P = 0.04). These results suggest that PA-treated exosomes caused an increase in basal inflammatory state of MDM but made them refractory to further inflammatory stimuli. Alterations in circulating metabolites may have both direct and indirect effects on inflammatory signaling, and further investigation of exosome signaling may contribute to our understanding of immune function during times of stress.