Depression is a common psychiatric condition with a considerable influence on global health. Although current pharmacotherapeutic choices are of indisputable relevance, there is sustained interest in natural medicines for treating depressive symptoms. Polyphenols, a class of plant-derived natural compounds, have received attention due to their possible neuroprotective and anti-depressive properties. In this review, we aimed to present the intricate mechanisms through which polyphenols modulate inflammation, neurogenesis, oxidative stress, and the gut microbiota. Consumption of polyphenol-rich diets is emerging as a non-invasive, natural, and cost-effective approach to supporting brain health, with potential influence on depressive symptoms. While there have been promising results, more research is needed to draw solid conclusions regarding the medicinal potential of polyphenols.