〔Abstract〕 To investigate the effects of hypoxia-treated mesenchymal stem cell (MSCs) exosomes (Exo) and their loading with curcumin on microglial inflammatory responses, and to explore the enhancing effect of hypoxia treatment on the function of MSCs Exo. Methods The supernatants of hUC-MSCs cultured under normal and hypoxic conditions were collected, and Exo were isolated using ultracentrifugation. After identification by transmission electron microscopy and Western blot, curcumin was loaded using the co-incubation method. The lipopolysaccharide (LPS)-induced microglial inflammation model was treated with dimethyl sulfoxide (DMSO), curcumin, normoxia Exo, hypoxia Exo, normoxic Exo loaded with curcumin, and hypoxic Exo loaded with curcumin, respectively. The expression of the M1-type marker inducible nitric oxide synthase (iNOS) in BV2 cells was detected by immunofluorescence (IF). Western blot and enzyme-linked immunosorbent assay (ELISA) were used to measure the expression and secretion levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in the cells and their culture supernatants. Results Normoxia Exo, hypoxia Exo, normoxic Exo loaded with curcumin, and hypoxic Exo loaded with curcumin exhibited a "saucer-like" shape with a diameter ranging from 30~150 nm, and the expression of exosomal markers CD9, CD81, and TSG101 were positive. After treating the BV2 cell inflammation model, IF results showed that, compared with the normoxia Exo group, treatment with hypoxic Exo significantly reduced the expression of iNOS. Moreover, when compared with the curcumin group and the normoxic Exo loaded with curcumin group, the expression level of iNOS significantly decreased after treatment with hypoxic Exo loaded with curcumin. The results of Western blot and ELISA indicated that, in comparison with the normoxia Exo group, treatment with hypoxic Exo significantly reduced the expression and secretion of the inflammatory cytokines TNF-α, IL-1β, and IL-6. Additionally, when compared with the curcumin group and the normoxic Exo loaded with curcumin group, both the expression and secretion of TNF-α, IL-1β, and IL-6 significantly decreased after treatment with hypoxic Exo loaded with curcumin. Conclusion Hypoxia preconditioning can enhance the ability of hUC-MSCs-Exo in the inhibition of microglial polarization and inflammatory factors, secretion. Additionally, using Hypoxia-MSCs-Exo as a drug-delivery carrier of curcumin can improve its solubility and stability, facilitating its absorption by cells and exerting the therapeutic effect of combination therapy.