Sepsis is the syndrome of systemic inflammatory response caused by infection. Over 20 million people worldwide suffer from sepsis each year, of whom about 6 million die, with a case-fatality rate of more than 25%. Therefore, to develop a rational plan for the management of sepsis, there is an urgent need to understand the mechanism of pathogenesis. Sesamin is a kind of sesame lignin isolated from sesame that exhibits multiple biological functions including antiviral, antidyslipidemic, and antihypertensive to name a few. An antioxidant and anti-inflammatory activity of sesamin appears to be a common denominator in all of its biologic activities. However, the mechanism of sesamin on septic-induced acute pulmonary inflammation still needs further study. Herein, we have established a sepsis model of C57BL/6 mice by cecal ligation and perforation. Using this model, we have shown that sesamin could reduce the levels of several inflammatory factors as well as oxidative stress response. Furthermore, sesamin could repress NLRP3 inflammasome and activate Nrf2/HO-1 pathway, and further inhibit acute pulmonary inflammation. This study reveals the mechanism of the diminution of septic-induced acute pulmonary inflammation by sesamin. This opens a theoretical basis for the development of drugs for treatment of sepsis.