St. John’s wort (SJW, Hypericum perforatum ) is noted for its potential in treating mild to moderate depression, attributed to its active compounds, hypericin and hyperforin. These compounds boost neurotransmitter levels—serotonin, norepinephrine, and dopamine—enhancing mood regulation and symptom relief. Also, SJW has anti-inflammatory and neuroprotective effects. Clinical evidence supports its efficacy for mild to moderate depression, showing comparable results to selective serotonin reuptake inhibitors (SSRIs), though its effectiveness in severe depression is less certain. SJW has common side effects like gastrointestinal issues and photosensitivity and poses serious risks due to interactions with medications, which can reduce the efficacy of drugs such as anticoagulants and hormonal contraceptives and lead to serotonin syndrome. Globally, it is classified as an herbal medicine or dietary supplement, with varying regulatory status and quality control issues. Ethical concerns include its use in vulnerable populations and the need for informed consent due to variable quality and interactions. In clinical practice, SJW is utilized for mild to moderate depression, either as an adjunct to conventional treatments or as a standalone therapy. Standard treatments for psychological disorders usually include pharmacotherapy, brain stimulation, and psychotherapy. However, many patients opt for alternative treatments like nutraceuticals or dietary supplements due to drugs’ \RL side effects, dependency, withdrawal symptoms, and the high costs of conventional options. Factors such as lack of insurance, social stigma, non-adherence, and dissatisfaction with traditional treatments often drive this preference. This review evaluates its use in major depressive disorder (MDD), focusing on long-term efficacy, safety, and potential personalized medicine approaches. Innovations in combination therapies, delivery methods, and biomarkers may enhance therapeutic outcomes. SJW and complementary therapies offer additional options, particularly for patients resistant to conventional treatments, given that standard antidepressants may not address all underlying factors of MDDs, such as inflammation and nutritional deficiencies.