Microglia and astrocytes interpret and propagate inflammatory signals initiated in the periphery, coordinating communication between the immune system and the brain. These biochemical, physiological, and morphological changes in activation influence behavior and cognition. One issue in glial biology is that analysis of morphology alone is used to interpret the activation state of glia. Therefore, the purpose of this study was to determine behavior and the corresponding activation (mRNA and morphological) profiles of microglia and astrocytes 0-72 h after acute lipopolysaccharide (LPS) injection. Here we show that LPS injection in mice induced sickness behavior with reduced locomotor activity and social exploratory behavior. This behavioral response was transient and resolved within 24-48 h after LPS. Acute LPS injection also sufficiently activated both microglia and astrocytes with a time dependent increase in mRNA expression of IL-1b, IL-6, CCL2, and TNFa. Specifically, the height of cytokine mRNA expression after LPS was at 4 h in microglia and 12 h in astrocytes. Moreover, analysis of M1 and M2 markers in the brain did not provide evidence for a M1 to M2 transition with the recovery from sickness. While astrocytes had increased cytokine mRNA expression, no changes in GFAP labeling were detected. Microglial morphological alterations were detected with increased Iba-1 immunoreactivity, but these were only evident at 24 and 48 h after LPS. Overall, this study indicates that activation and corresponding cytokine production by glia precedes alterations in morphology following transient activation of the immune system.