Tyloxapol is a surfactant which increases the concentration of lipoproteins in humans and animals. These lipoproteins are the natural scavengers of the lipopolysaccharides, also known as endotoxins, secreted by outer membrane of the gram-negative bacterium and responsible for morbidity and mortality of the diseases associated with gram-negative bacterium. Therefore, the present study was designed to evaluate the therapeutic effects of tyloxapol in Pasteurella multocida-induced infection in water buffaloes. For this purpose, 12 healthy buffalo calves, 8-10 months old, were procured and experimentally induced with Pasteurella multocida infection after acclimatization period of 7 days. The buffalo calves were randomly divided into two groups (n=6) A & B. Group A was treated with ceftiofur HCl and flunixin meglumine @ 6 and 2 mg/kg BW, respectively. This treatment continued for 5 days. Group B was administered with tyloxapol @ 150 mg/kg BW IV QD continuously for 3 days. Efficacy of the treatment was evaluated through cardinal parameters, lipoproteins and concentrations of cytokines and endotoxins. The data obtained was analyzed statistically. Results of the study depicted that no untoward or allergic reaction was observed after intravenous administration of tyloxapol to the buffalo calves. Tyloxapol significantly elevated lipoprotein concentrations to the normal in group B and differed significantly (P<0.05) from its counterpart. It significantly (P<0.05) reduced the concentration of pro-inflammatory cytokines and endotoxins than its counterpart, thereby successfully ameliorated their deleterious effects. We concluded from findings of the study that tyloxapol is safe to administer in buffalo calves and could successfully resuscitate the calves suffering from hemorrhagic septicemia thus improving survival. It showed anti-endotoxic effects and enhanced natural scavengers of endotoxins i.e., HDL & LDL and successfully ameliorated cytokine concentration. Tyloxapol can be useful in clinical settings to contravene the effects of endotoxemia/septicemia in animals.