Background: Chronic obstructive pulmonary disease (COPD) is mainly induced by the increased content of particulate matter 2.5 (PM2.5) in the atmosphere. This study aimed to evaluate the effects of betulinic acid derivative on lung inflammation in a mouse model of chronic obstructive pulmonary disease induced by particulate matter 2.5. Material/Methods: The mice were given a PM2.5 (25 μl) suspension for 7 days by the intranasal route to establish a COPD model. The content of TNF-a and IL-6 in the BALF samples was measured by commercially available ELISA kits. Results: The PM2.5-induced higher LDH and ACP levels were significantly alleviated in mouse lung tissues by treatment with betulinic acid derivative. Treatment with betulinic acid derivative also suppressed PM2.5-induced increase in AKP and ALB levels in mouse lung tissues. Betulinic acid derivative reversed PM2.5-mediated suppression of SOD activity and elevation of NOS level in mouse BALF. Moreover, the PM2.5-induced excessive NO and MDA levels in mouse BALF were significantly reduced (P<0.05) by treatment with betulinic acid derivative. Treatment with betulinic acid derivative improved TNF-a and IL-6 levels in BALF induced by PM2.5 exposure. Betulinic acid derivative inhibited PM2.5-induced acute inflammatory exudate, alveolar septae damage, and inflammatory cell infiltration in lungs of mice. Conclusions: In the mouse model of PM2.5-induced COPD, betulinic acid derivative reduced the degree of lung inflammation and downregulated inflammatory mediators. These findings support the need for further in vivo studies and clinical evaluation of betulinic acid derivative in patients with COPD. © Med Sci Monit, 2020