Background: Lifestyle modifications (physical activity and diet) are among the most promising strategies in multiple sclerosis (MS) rehabilitation. This study aimed to investigate the effects of combined home-based AT and Vit D on the neurotrophins level and biomarker of inflammation in MS patients during COVID-19 outbreak., Methods: In this randomized, single-blinded, placebo-controlled trial, 38 females with MS having EDSS: 3-5 (aged 20-40 years with body mass index [BMI] of 25-30 kg/m 2 ) were randomly assigned into four groups: AT+Vit D (n = 10), AT (n = 9), Vit D (n = 9), and Control (C n = 10). The AT program consisted of 50-70% of HR Max , 25-40 min/day, three days/wk for eight weeks. Participants in the Vit D group consumed 50,000 IU of Vit D supplement capsules per week for eight weeks. The data were analyzed through paired t-test and one-way analysis of variance and Tukey's post hoc test at the signification level of P<0.05., Results: AT+Vit D, AT, and Vit D compared to the control, increased BDNF and NGF, and downregulated CRP, TNF-a, IL-6, and IL-1β in MS patients. Additionally, the AT+Vit D group showed significantly lower CRP, TNF-a, IL-6, and IL-1β levels and significantly higher BDNF and NGF levels compared to the AT and Vit D groups. Also, the results of this study showed significant differences between AT and Vit D groups in the variable mentioned above., Conclusions: These findings suggest that AT+Vit D improves neurotrophin and inflammatory biomarker levels in female MS patients more effectively than AT or Vit D alone., (Copyright © 2022 Elsevier B.V. All rights reserved.)