Depression, or Major Depressive Disorder (MDD), is a common and serious psychiatric disorder characterized by persistent sadness, loss of interest, and cognitive and physical disturbances. Despite the availability of several antidepressant drugs such as SSRIs, SNRIs, TCAs, and MAOIs, many patients experience delayed response, adverse effects, or treatment resistance. Therefore, the search for new therapeutic strategies remains essential. Phenothiazine, a tricyclic heterocyclic scaffold containing nitrogen and sulfur atoms, has long been used in medicinal chemistry, particularly for antipsychotic and antihistaminic drugs. Recent studies suggest that certain phenothiazine derivatives may exhibit antidepressant potential by modulating multiple neurotransmitter systems including dopamine, serotonin, and norepinephrine. This review highlights the neurobiology of depression, structural features and synthesis of phenothiazine, structure–activity relationships, mechanisms contributing to antidepressant effects, and preclinical evaluation models. It also discusses the current clinical status and future prospects of phenothiazine-based compounds in antidepressant drug development.