Objectives: This study aimed to evaluate the effects of vitamin D and/or magnesium supplementation on mood, serum levels of BDNF, inflammation, and SIRT1 in obese women with mild to moderate depressive symptoms. Methods: In this trial, the 108 obese women with mild to moderate depressive symptoms were randomly allocated into 4 groups: (1) co-supplementation group (n = 27): receiving a 50000 IU vitamin D soft gel weekly + a 250-mg magnesium tablet daily; (2) vitamin D group (n = 27): receiving a 50000 IU vitamin D soft gel weekly + a magnesium placebo daily; (3) magnesium group (n = 27): receiving a vitamin D placebo weekly + a 250-mg magnesium tablet daily; (4) control group (n = 27): receiving a vitamin D placebo weekly + a magnesium placebo daily, for 8 weeks. Before and after the intervention, anthropometric indices, depressive symptoms, serum levels of BDNF, 25(OH)-D, inflammation, and SIRT1, were measured. Results: At the end of the study, ANCOVA demonstrated significant differences between the 4 groups in 25(OH)-D, magnesium, TNF-alpha, IL-6, and BDNF levels. But, we found no significant differences in terms of hs-CRP and SIRT1 levels. A significant reduction in depression score was observed in 3 intervention groups and also in control group. No significant differences in BDI-II score were shown among the 4 groups at the end of the intervention. Conclusion: Vitamin D plus magnesium supplementation in obese women with mild to moderate depressive symptoms has beneficial influences on mood, serum levels of BDNF, inflammation, and SIRT1.