Objective: To identify early changes in hippocampal quantitative parameters in multiple sclerosis (MS) patients using synthetic MRI, and to correlate these changes with clinical variables. Methods: 45 MS patients and 26 healthy controls (HCs) underwent synthetic MRI and 3D-T1 MRI. The hippocampus volumes were assessed by using voxel-based morphometry. Synthetic MRI parameters (T1, T2, and proton density (PD)) from hippocampus and its subfield were measured and compared, and their associations with the Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT) scores were further investigated. Results: There was no significant difference in hippocampal volume between MS patients and HCs. Compared with HCs, the T1, T2 and PD values of hippocampus and its subfield increased in MS patients. T2 values showed positive correlation with EDSS and negative correlation with SDMT. Conclusions: Synthetic MRI can detect subtle quantitative changes of the hippocampus in MS patients with normal hippocampal volume. Specifically, Synthetic MRI parameters may apply as potentially effective imaging biomarker for hippocampus evaluation.