Our study aims to determine the effects of alamandine, the newest component of the renin-angiotensin system, on cognitive functions, neuroinflammation, and oxidative stress in the pathophysiology of depression. 35 male Sprague dawley rats, three months old, weighing between 300 and 350 g, were used. The chronic, unpredictable mild stress model of depression was performed. Experimental animals were divided into five groups: control (C), depression (D), alamandine (50 µg/kg, ip) (D + ALA), A779 (300 µg/kg, ip) (D + A779), and both alamandine and A779 treatment groups (D + ALA + A779). After confirming the development of depression through behavioral tests, the animals' learning and memory performances were measured using the Morris water maze test. At the end of the experiment, the animals' prefrontal cortex, hippocampus, and blood samples were isolated for biochemical studies and gene expression analyses. The sucrose preference, open field, elevated plus maze, tail suspension, and forced swimming tests were performed to determine the animals' anxiety levels. There was a significant increase in anxiety-like behaviors in the D group and the A779-treated group, while alamandine exhibited an anxiolytic effect. Moreover, improvements in cognitive skills observed in the Morris water maze test were paralleled by molecular changes, including an increase in BDNF protein levels and NMDA receptor expression and a decrease in GABA levels. In addition, the levels of TNF-α, IL-1β, IL-6, and oxidative stress markers were increased in the depression groups while significantly decreased with alamandine treatment. It was concluded that alamandine has an anxiolytic effect and facilitates spatial memory by reducing neuroinflammation and oxidative stress.