Hypericum perforatum, also known as St. John’s Wort, pericon, or yellow grass, is known for its antidepressant potential. It could represent a natural alternative to current pharmacological antidepressant treatments, which have a high incidence of side effects in patients and therefore lead to early dropouts. Through a bibliographic revision of clinical trials and information collected from scientific articles during the first period of 2020, we aimed to evaluate whether its administration could be beneficial in the treatment of mild-to-moderate depression, with fewer side effects compared to synthetic drugs. Among the main components, hypericin and hyperforin have been related to the observed antidepressant activity; therefore, their possible mechanism of action was reviewed and highlighted. Furthermore, patients receiving Hypericum extracts were less likely to withdraw from studies because of adverse effects compared to those receiving older standard antidepressants. This review aims to provide suggestions for an alternative treatment of mild-to-moderate depression disorder under the supervision of a medical doctor, since, although it appears to be a potentially efficient treatment with a low presence of adverse effects in comparison to synthetic antidepressants, it might also interact with other medications and lead to therapeutic failures if misused for self-medication.