Chronic airway inflammation is a characteristic feature of chronic obstructive pulmonary disease (COPD). Previous studies demonstrated that melatonin had a protective effect against COPD. In addition, silent information regulator 1 (SIRT1) was reported to be beneficial in COPD. However, whether SIRT1 is involved in the protective effect of melatonin against COPD remains unclear. In this study, we investigated the effect of melatonin on a rat model of COPD and explored the potential mechanisms. Twenty eight male Wistar rats were randomly assigned to four groups: control group, COPD group, COPD+Mel group and COPD+Mel+EX527 group. Rats were challenged with cigarette smoke and lipopolysaccharide (LPS) for 28 days with or without melatonin or EX527. The pulmonary function, lung histopathology, inflammatory cells count and the concentration of IL-1β in the BALF as well as the protein expressions of SIRT1, NLRP3, cleaved caspase-1 and ASC in the lung tissues were measured. The results demonstrated that melatonin prevented the development of COPD, which was attributed to the inhibition of airway inflammation by attenuating NLRP3 inflammasome and IL-1β. Furthermore, melatonin increased the expression of SIRT1 in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 abolished the protective effect of melatonin against COPD. In conclusion, these findings suggested that melatonin attenuated airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1β in rats with COPD.