One of the most complex clinical challenges facing medical practice is sepsis-induced lung dysfunction resulting from polymicrobial sepsis. Although many therapeutic approaches have been used in such clinical challenges, there is still further need for a new effective therapeutic approach. The objective of this study was to investigate if Montelukast could protect the lungs during polymicrobial sepsis by regulating inflammatory markers and the oxidative stress pathways. Twenty-four mature male Swiss-albino mice aged 8–12 weeks, with a weight of 20–30 g, were randomized into 4 equal groups (n=6), sham (laparotomy without cecal ligation and puncture (CLP)), CLP (laparotomy with CLP), vehicle 1 (equivalent volume of DMSO 1 hour prior to CLP), Montelukast (10 mg/kg IP 1 hour prior to CLP). Lung tissue pro-inflammatory mediators IL-6, IL-1β, IL-17, LTB-4 12(S) HETE, and oxidative stress were assessed using ELISA. The levels of F2 isoprostane were considerably greater in the sepsis group (p<0.05) as compared to the sham group, while Montelukast was significantly lower (p<0.05) in these inflammatory mediators and oxidative stress as compared to the sepsis group. Histologically, the lung tissue damage was significant (p<0.05) in all mice in the sepsis group, while Montelukast significantly reduced lung tissue injury (p<0.05). The current findings indicated that Montelukast could attenuate lung dysfunction during CLP-induced polymicrobial sepsis in male mice through their modulating effects on pro-inflammatory and oxidative stress downstream signalling pathways and subsequently decrease lung tissue cytokine concentrations (IL-1β, IL-6, IL-17, LTB-4, and 12(S)HETE).