Aim To investigate the effect and mechanism of paeonol on the secretion of exosomes in THP-1 cells induced by lipopolysaccharide (LPS). Methods THP-1 cell culture supernatant exosomes were extracted by ultracentrifugation; the morphology of exosomes was observed by transmission electron microscope (TEM), and the marker proteins Alix, TSG101, CD9 and CD63 were detected by Western blot, and the dynamic light scattering (DLS) was used to detect exosome particle size. CCK-8 was used to detect the effect of different concentrations (0,0, 1,0.1,0.01 and 0.001 mg/L) of LPS on the survival rate of THP-1 cells to determine the optimal concentration; CCK-8 was used to detect the survival rate of THP-1 cells in different concentrations of paeonol (0,0, 0,0 and 15 μmol/L) medium for different time (2,4 and 48 h), to determine the optimal concentration and time; the amount of exosome protein was detected by BCA; the levels of N-SMase2 and p38 MAPK proteins in the cells were detected by Western blot. Results The results showed that the microvesicle structure obtained by ultracentrifugation was exosome. When the dose of LPS was 1 mg/L, it was suitable; when paeonol was administered at 60 μmol/L, the cell survival rate was higher at 24 h. The exosome secretion of the LPS group was significantly increased compared with the blank group, and the N-SMase2 protein level was increased, and the effect was similar to that of DNR. The exosome secretion of the paeonol group was significantly reduced compared with the LPS group, and the expression of N-SMase2 protein was decreased, and the effect was similar to that of GW4869. LPS promoted phosphorylation of p38 MAPK, and paeonol and SB203580 inhibited p38 MAPK phosphorylation.Paeonol inhibited the secretion of exosome of THP-1 cells after LPS stimulation. Conclusion Paeonol inhibits the secretion of THP-1 cell exosome, which is related to the inhibition of p38 MAPK/N-SMase2 pathway.