Background: There is no information about the effects and usability of rehabilitation during corticosteroid treatment. This randomized clinical trial was conducted to evaluate and compare the effects and safety of exergaming and conventional rehabilitation (CR) on persons with multiple sclerosis (MS, pwMS) during corticosteroid treatment. Methods: The participants were randomly divided into two groups: Exergaming (n=15) and CR (n=15). Rehabilitation was applied by a physiotherapist who has expertise in MS. Measurements were done at baseline (T1), immediately after discharge (T2), and 1 month after discharge (T3). The outcome measures included upper extremity functions, walking, balance, cognitive functions, quality of life, depression, and fatigue. Results: The Nine Hole Peg Test, California Verbal Learning Test, Symbol Digit Modalities Test, MS Walking Scale 12, Six Spot Step Test showed a significant difference between T1 to T2 and T1 to T3 in the exergaming and CR groups (p < 0.05). The Timed 25 Foot Walk and Multiple Sclerosis International Quality of Life Questionnaire were significantly different between T1 to T3 in the exergaming and CR groups (p < 0.05). Brief Visuospatial Memory Test-Revised was significantly different between T1 to T3 and T2 to T3 in the exergaming and CR groups (p < 0.05). The MFIS showed a significant difference between T1 to T2 and T1 to T3 in the exergaming group (p < 0.05). Conclusions: This study suggests that exergaming and CR are effective and safe methods for improving upper extremity, cognitive functions, fatigue, quality of life, balance, and walking ability in pwMS during the hospitalization period.