Major Depression Disease is a common mental illness that affects more than 322 million people worldwide and it is one of the leading causes of mental and physical disability. The etiology of depression is a complex interplay of psychological, social, and biological factors. Currently, psychopharmacotherapy is based mainly on the monoamine theory, which states that depression is caused by an insufficient level of monoamines such as serotonin, norepinephrine, and/or dopamine. Due to the relatively low efficacy of the typical antidepressant and the high prevalence of treatment-resistant depression (~30%), seeking new ways of prophylaxis, adjuvant therapy, or novel compounds with antidepressant activity, is a priority. According to studies that analyzed mushroom consumption patterns and depression prevalence, it was concluded that mushroom ingestion lowers the odds of depression. Medicinal mushrooms are considered functional foods because of their ability to synthesize and accumulate different types of metabolites, which enhance their health-promoting properties. The review aims to explain the antidepressant activity of edible/medicinal mushrooms by elucidating the mechanism from different perspectives: edible mushrooms as a source of serotonin precursors and psilocybin as a rapid-acting antidepressant. These compounds exhibit anti-neuroinflammatory and antioxidant activities that impact neurotrophin expression, the neurogenesis process, and influence on the gut–brain axis.