Depression, the most common type of mental illness, is the second leading cause of disability and is increasing among Americans. The effect of improved nutrition, particularly with dietary supplements, on depression may provide an alternative to standard medical treatment. Some studies have shown that certain nutrients (e.g., inositol and S-adenosyl methionine) are effective at improving depressed mood, although the results are not unequivocal. The current study was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a vitamin B complex nutritional supplement (Max Stress B) for improving depressive and anxiety symptoms according to the Beck Depression and Anxiety Inventories (BDI and BAI) in 60 adults diagnosed with major depression or other forms of depressive disorders. Secondary outcomes included quality of life according to the SF-36. Participants were assessed at baseline and 30- and 60-day followups. Max Stress B showed significant and more continuous improvements in depressive and anxiety symptoms, compared to placebo. Additionally, Max Stress B showed significant improvement on the mental health scale of the SF-36 compared to placebo. Thus, we showed modest utility of Max Stress B to improve mood symptoms and mental health quality of life in adults with depression.