Orexin neurons in the lateral hypothalamus constitute a critical component in regulation of waking, feeding, and reward-related behaviors. In this study we examined the effects of lipopolysaccharide (LPS) challenge on Fos expression in orexin neurons in rats, to determine changes during sickness in two different behavioral contexts. One cohort of rats was treated with saline or LPS during the daytime, and then tested on an elevated plus maze (EPM) or left in their home cage until sacrifice. Another cohort received LPS or saline shortly before dark onset and was sacrificed 90min into the dark period. The brains were double-stained for Fos and orexin-A immunoreactivity (both cohorts) and for Fos and histidine decarboxylase (dark period cohort). Orexin neurons were strongly activated in context of exploratory behavior (double-labeled for Fos in both medial and lateral portions). LPS challenge prior to maze exposure diminished this activation, most notably among the lateral orexin neurons. In home cage controls, LPS challenge lead to increased Fos expression, most notably in the medial orexin neurons, when compared to saline-injected home cage controls that show little or no Fos during the daytime. In the dark period, Fos expression in both orexin and histaminergic neurons was abundant, which LPS challenge strongly suppressed. These findings are consistent with the hypothesis that the orexin neurons, in conjunction with the histaminergic system, represent a potential target of the neurocircuitry that drives sickness behavior due to peripheral inflammation, likely through functional inhibition of these hypothalamic cell groups.