Objective To investigate whether mesenchymal stem cell-derived exosomes (MSC‑Exo) regulate ferroptosis by modulating the JAK2/STAT3 signaling pathway to alleviate hypoxia/re-oxygenation (H/R)-induced oligodendrocyte injury. Methods Oligodendrocytes were randomly divided into control, H/R, and MSC‑Exo groups. Except for the control group, cells underwent H/R treatment. Western blot analysis was used to detect protein expression of oligodendrocyte markers (MAG, Olig2, MOG, MBP), exosome markers (TSG101, CD81, CD63), endoplasmic reticulum protein (calnexin), ferroptosis-related proteins (GPX4, TFR), and JAK2/STAT3 signaling pathway components (JAK2, p-JAK2, STAT3, p-STAT3). Cell viability was assessed by CCK-8 assay. Spectrophotometric methods were employed to measure caspase-3 activity, glutathione (GSH) content, Fe²⁺ levels, and malondialdehyde (MDA) concentrations. Apoptosis and reactive oxygen species (ROS) production were analyzed by flow cytometry using Annexin-V/PI double staining. To verify the role of JAK2/STAT3 pathway in MSC‑Exo-mediated inhibition of ferroptosis, a JAK2 inhibitor (JAK2i) was applied, and cells were assigned to H/R, MSC‑Exo, JAK2i, and JAK2i + MSC‑Exo groups. The protein expression levels of GPX4, TFR, p-JAK2, and p-STAT3, as well as cell viability, GSH, Fe²⁺, MDA, apoptosis, and ROS production, were determined using the aforementioned methods. Results Compared with the control group, the H/R group showed significantly decreased cell viability and GSH content, and increased ROS, MDA, Fe²⁺, and apoptosis (P<0.05). Protein levels of TFR, p-JAK2, and p-STAT3 were significantly upregulated, while GPX4 was downregulated (P<0.05). Compared with the H/R group, both JAK2i and MSC‑Exo treatments significantly inhibited p-JAK2, p-STAT3, and TFR expression, upregulated GPX4 expression, increased cell viability and GSH content, and reduced ROS, MDA, Fe²⁺, and apoptosis levels (P<0.05). Conclusions MSC‑Exo inhibit ferroptosis by suppressing the JAK2/STAT3 signaling pathway, thereby alleviating H/R-induced oligodendrocyte injury.