Background: Inflammatory cytokines are released in response to cell injury. Liver is very susceptible to injury while serving its functions. It can be injured by several aetiological agents such as toxin, infectious agents, chemical and drugs including paracetamol (PCM). Aims: The present study was aimed to determine the changes of plasma inflammatory cytokines due to PCM-induced liver injury and the effect of Plantago major leaf extract on these changes. The changes of 11-β hydroxysteroid dehydrogenase type 1 (11-β HSD1) enzyme in the liver was also determined as it involves in conversion of inactive glucocorticoid to active form or vice versa. Methods: Thirty male Sprague Dawley rats were divided into control (C) and PCM-induced groups. The latter was subdivided into PCM without treatment (PCM), PCM with aqueous extract (PCM +AQ) and PCM with ethanol extract (PCM+ ET). The PCM (2 g/kg) was given to the rats via intragastric tube. The plant extract (1 g/kg) was given orally for 6 days after 24 hours of PCM induction. Plasma was collected to examine the interleukin (IL) 1α, 1β, 6 and 10, and tumour necrosis factor-α (TNF-α) while the liver tissue was prepared for 11-β HSD enzyme study. Results: Our results revealed the increased level of IL 1α, 1β and TNF-α in PCM group and this changes was attenuated by the extract treatment. There was no significant change in IL6 and IL10 among all groups. The 11-β HSD1 activity and expression were reduced in PCM and it was corrected with the extract treatment. Conclusion: The Plantago major leaf extract treatment attenuated the liver injury by reducing the proinflammatory cytokines and the changes of 11-β HSD1 activity and expression might link to the liver regeneration process and plasma cytokine level changes.