Abstract: Major depressive disorder (MDD), as the most common and typical clinical manifestation of depression, is one of the leading causes of disability worldwide, imposing a significant burden on both society and individuals. Currently, commonly used antidepressants in clinical practice are characterized by limitations such as slow onset of action, low response rates, and numerous adverse effects, underscoring an urgent need for the development of safer and more effective innovative therapies. Against this backdrop, the research and development of antidepressants have undergone four generations of evolution. The first-generation drugs includes monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). While these drugs were groundbreaking, their clinical application has been limited due to severe adverse effects. To enhance safety, the second generation of drugs emerged, represented by selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and norepinephrine and dopamine reuptake inhibitors (NDRIs). However, these drugs still face challenges such as inadequate response and sexual dysfunction. Building on this, the third-generation drugs, characterized by multimodal antidepressants that combine monoamine reuptake inhibition with receptor modulation, as well as serotonin, norepinephrine, and dopamine reuptake inhibitors (SNDRIs), have shown certain advantages in improving core symptoms such as anhedonia and cognitive dysfunction, and accelerating onset of action. In recent years, research breakthroughs have given rise to the fourth-generation drugs based on novel mechanisms. Among these, esketamine and AXS-05, which act on the glutamatergic system, and zuranolone, which targets the GABAergic system, have demonstrated rapid and robust antidepressant effects, effectively addressing the urgent clinical need for rapid symptom relief and reduction of suicide risk. This review systematically traces the iterative development of antidepressant drugs, from serendipitous discovery to rational design and beyond the monoamine hypothesis. It provides an thoroughly analysis of the R&D background, mechanisms of action, clinical advantages, and limitations of each generation of drugs, aiming to provide references and insights for the development of novel drugs.