Major depression disorder is increasing globally, causing great personal suffering and economic burdens to society. Current antidepressant medications are not sufficiently able to treat all cases of depression and are often associated with troubling side effects. There is a great need for the development of novel treatments, and classic psychedelic drugs are currently being investigated with new interest. The legal status has hindered research, but promising results from pioneering studies on the antidepressant effect of psilocybin have recently given psilocybin breakthrough therapy status, allowing further research to occur more freely. This systematic review aims to investigate the literature available on psilocybin’s effect on major depressive disorder. Five studies were selected according to set inclusion and exclusion criteria. Results are suggesting that psilocybin combined with psychological support is a fast-acting antidepressant agent, able to produce a sustained decrease in symptoms of depression with minimal side effects. However, current studies come with several limitations and further research is needed before the antidepressant effect of psilocybin can be stated as a fact.