Depression, a debilitating mood disorder characterized by persistent sadness and anhedonia, affects millions worldwide, yet available therapies remain suboptimal and often cause undesirable side effects. Emerging evidence highlights the crucial role of gut microbiota in regulating mental health through the gut-brain axis, paving the way for novel therapeutic strategies. As per preclinical and clinical studies, there is a causal relationship between gut dysbiosis and depression via modulation of brain activity through the gut-brain axis (GBA), and the key to targeting microbes is key to treating depression. Postbiotics-bioactive compounds derived after fermentation have been shown to provide several health benefits, particularly in terms of neuroinflammation, neurotransmitter imbalance, mitochondrial dysfunction, and restoration of neuroplasticity associated with depression. This review explores the neuroprotective mechanisms by which postbiotics alleviate depression, including the modulation of neurotransmitter synthesis, suppression of neuroinflammation, mitigation of oxidative stress and mitochondrial dysfunction, and restoration of neuroplasticity. Furthermore, postbiotics hold potential as adjuvant therapy alongside conventional antidepressants, enhancing treatment efficacy and minimizing side effects. Despite promising initial findings, challenges such as standardized formulation, clinical dose optimization, and regulatory framework development must be addressed. Large-scale clinical trials are imperative to validate their therapeutic potential and facilitate integration into mainstream depression management. As research advances, postbiotics may redefine mental health treatment, emerging as a revolutionary microbiome-based approach for long-term patient care.