Neuroinflammation affects dopamine metabolism and produces a set of symptoms known as sickness behavior, including fever, anhedonia, anorexia, weight loss, decreased sociability and mobility, and cognitive impairment. Motor and cognitive impairments related to sickness behavior are associated with dopamine (DA) metabolism imbalance in the prefrontal cortex. Lipopolysaccharide (LPS) administration induces neuroinflammation and causes sickness behavior in mice, while physical exercise has anti-inflammatory properties and may attenuate sickness behavior and DA impairment. We investigated the effect of exercise on DA levels and sickness behavior induced by LPS in mice. Adult Swiss male mice (8ndash;10 weeks, 47.1plusmn;0.7 g, n=495) performed six weeks of voluntary exercise in free-running wheels (RW group) or had the blocked wheel in their cages (sedentary, SED group). After six weeks of exercise, both groups received an intraperitoneal injection (i.p.) of either saline (SAL) or LPS (0.33 mg/kg, i.p.). All animals were submitted to behavioral tests for sickness behavior assessment (fatigue, locomotion, anhedonia, and social interaction). Neuroinflammation markers and DA metabolism were assessed in the prefrontal cortex. LPS administration provoked anorexia, body weight loss, impaired motor function, social withdrawal, and anhedonia. This sickness behavior was accompanied by reduced cortical DA metabolism and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC). Neuroinflammation was confirmed through increased levels of the proinflammatory cytokines IL-1beta; and IL-6. Inflammation was also confirmed in the blood by an increased content of IL-1beta;. Physical exercise intervention prevented animals from neurochemical, biochemical, and behavioral alterations. These findings provide new evidence of physical exercise's potential as an environmental approach to treating neuroinflammatory conditions.