Purpose of the Review <p>The review summarizes widely accepted theories of Major Depressive Disorder (MDD) pathogenesis including Neurotransmitters and receptor hypothesis, Hypothalamic–pituitary–adrenal (HPA) axis hypothesis, Cytokine and oxidative stress (OS) hypothesis, Neurotrophic factors and neuroinflammation. However, none can entirely explain the disorder’s complex and heterogeneous nature. While traditional antidepressants remain efficacious in treatment of depression nevertheless, it is essential to balance their benefits against the potential adverse effects. The update further provides an overview on recent clinical trials involving both conventional antidepressants and emerging medications. Preventive therapies like nutrient rich diet, regular exercise and social interventions which play a crucial role in mitigation of depressive symptoms have also been incorporated. This review comprehensively consolidates the latest research on disease etiology, pathogenesis and clinical management of MDD.</p> Recent Findings <p>In recent years, significant advancements have been made in development of new antidepressants, with several already introduced into clinical trials.</p> Summary <p>This comprehensive review holds the potential to advance our understanding of etiology, pathogenesis and clinical management of MDD, thereby upgrading our knowledge base in neuroscience. Although the review is multidimensional in nature, future research should emphasize on incorporating digital health technologies and holistic care models to restructure the treatment landscape. Moreover, there is need for more systematic reviews and meta-analyses from global perspectives to obtain exhaustive knowledge on MDD in diverse populations. This progression would increase the relevance and acceptability of findings in the clinical practice.</p>