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However, due to incomplete mechanistic understanding, existing therapeutic strategies frequently yield suboptimal outcomes. This review synthesizes evidence establishing neuroinflammation as a central pathogenic mechanism of MDD, involving elevated proinflammatory cytokines, microglial M1 polarization, blood\u2013brain barrier (BBB) disruption, hypothalamic\u2013pituitary\u2013adrenal (HPA) axis dysregulation, and impaired neuroplasticity. Micro ribonucleic acid (miRNA) are identified as master molecular regulators bridging neuroinflammation and MDD pathology with details of how specific dysregulated miRNAs orchestrate MDD processes by targeting key inflammatory pathways, directing microglial polarization states, mediating intercellular communication via exosomes, and modulating BBB integrity. Crucially, these miRNAs may serve as novel diagnostic biomarkers and therapeutic targets for MDD. Building on this, we explore the potential of natural compounds as innovative miRNA\u2010targeting therapeutics that can ameliorate neuroinflammation and restore neuroplasticity. Current challenges relating to clinical translation are discussed, including discordance between peripheral and brain miRNA profiles, species\u2010specific miRNA functional variations, limited biomarker specificity across psychiatric disorders, the absence of standardized clinical reference ranges, and the need for more effective delivery systems. 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