Let alone calorie restriction, life span extension in higher organisms has proven to be difficult to achieve using simple drugs. Previous studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. However, younger subjects (< 40 years of age) are infrequently prescribed nor self-medicating with antiaging drugs. Therefore, in the present study, we aimed at assessing the effect of long-term treatment with spermidine given in the drinking water on behavioral performance and longevity of male, middle-aged Sprague-Dawley rats. We report that spermidine given in the drinking water did not extend neither the median nor the maximum life span of the middle-aged male Sprague-Dawley rats. However, spermidine treatment had a beneficial effect on the body weight and the kidney tubules, liver, and heart morphology. Behaviorally, spermidine led to a reduction in anxiety and an increase in curiosity, as assessed by exploratory behavior. Moreover, long-term treatment with spermidine enhanced autophagy in the brain and led to a diminished expression of the inflammatory markers, Tgfb, CD11b, Fcgr1, Stat1, CR3, and GFAP mRNAs in several cortical region and hippocampus of the treated rats suggesting that one beneficial effect of the long-term treatment with spermidine is an attenuated proinflammatory state in the aged brain. Our results suggest that long-term treatment with spermidine increases health span of middle-aged rats by attenuating neuroinflammation and improving anxiety and exploratory behavior.