Objective To assess the effectiveness and safety of combining methylprednisolone with mycophenolate mofetil in managing moderate to severe active Graves' ophthalmopathy （GO）， and to compare its efficacy against methylprednisolone monotherapy. Methods A retrospective study was conducted to select patients with moderate to severe active GO who received treatment at the Department of Endocrinology and Metabolism， Guizhou Medical University Affiliated Hospital， from January 2019 to January 2024. The patients were divided into two groups： a combination group receiving methylprednisolone combined with mycophenolate mofetil， and a monotherapy group receiving methylprednisolone alone. The objective was to compare changes in visual score， appearance score， clinical activity score （CAS）， eye protrusion， eye fissure width， and eye movement between the two groups of patients while documenting any adverse events. Results A total of 98 patients were enrolled in the study， comprising 32 patients in the combination group and 61 patients in the monotherapy group. Both groups exhibited improvements in quality of life scores， CAS， and degree of protrusion following treatment compared to baseline. However， at the end of the 12?week treatment period， there was no statistically significant difference （P > 0.05） observed between the two groups regarding changes in visual scores， appearance scores， CAS， protrusion degree， fissure width， and proportion of reduced eye movement before and after treatment. Notably though， the combined therapy group demonstrated a significantly higher improvement rate for pain relief and reduction of eyelid congestion during eye movement when compared to the monotherapy group （P < 0.001）. At the endpoint of treatment， there were no statistically significant differences in appearance score， protrusion degree， tear width， and reduction in eye movement between the two groups before and after treatment （P > 0.05）. The combination group exhibited higher visual scores and greater improvement in CAS compared to the monotherapy group （P < 0.05）， along with a higher rate of eyelid edema improvement （P < 0.05）. At 12 weeks， the monotherapy group had an effective rate of 65.0%， while the combination group had an effective rate of 66.7%. By week 24， the combined group achieved an effective rate of 80.0%. The overall effectiveness at week 12 and treatment endpoints did not show any statistically significant differences between the two groups （P > 0.05）. No cases of leukopenia or severe infection occurred in the combination group. Conclusions The combination therapy of methylprednisolone and mycophenolate mofetil demonstrates efficacy， tolerability， and safety in the treatment of moderate to severe active GO. While the overall effectiveness of this combination may not surpass that of hormone therapy alone， it exhibits potential superiority in improving visual scores， eyelid congestion， eyelid edema， and eye movement pain when compared to hormone therapy alone.