<p>Neurodegenerative disorders are an Critical worldwide issue, characterized by progressive neuronal loss and cognitive decline with limited effective therapies. A central problem in these conditions is chronic neuroinflammation, oxidative stress, and disrupted cellular homeostasis. Polyamines, such as putrescine, spermidine, and spermine—small molecules—play vital roles in maintaining neuronal function, regulating autophagy, and protecting against cellular stress. Notably, spermidine-induced autophagy has emerged as a key mechanism linking polyamine metabolism to neuronal longevity and cognitive resilience. Recent studies highlight that probiotics and specific gut microbes can effectively modulate host polyamine production through the gut-brain axis, influencing neural health. This microbial modulation has been shown to restore polyamine balance, enhance antioxidant defenses, and reduce neuroinflammatory responses. Targeting microbiota-driven polyamine synthesis is emerging as a promising, non-invasive approach for neuroprotection. This review consolidates the current understanding of polyamine biology and microbial influences, highlighting their therapeutic potential. Exploring these interactions offers new avenues for innovation in combatting neurodegenerative disorders.</p>