Platycodin D (PD) is the main active saponin of Platycodon grandiflorum (PG) and is reported to exhibit multiple biological effects, including anti-tumor, anti-inflammation, and anti-obesity properties. Although recently there have been many research reports on the chemical constituents of the plant's roots, only few works have been reported on the aerial parts of PG. In the present study, we report the first isolation of PD from the aerial parts of PG and its protective effect against acute alcohol-induced liver oxidative injury and inflammatory response in mice. In brief, the protective effect was evaluated by tracking biochemical markers, enzymatic antioxidants and proinflammatory cytokines in serum and liver tissue. The results indicated that PD pretreatment significantly decreased the levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (L-DLC) in serum and malondialdehyde (MDA) in liver. PD was also found to increase the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the liver (p < 0.05). In addition, PD markedly decreased the levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, which was caused by alcohol exposure (p < 0.05). In contrast, histopathological examinations revealed that PD pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and steatosis. Collectively, the present study clearly suggests that the protective effect exhibited by PD on alcohol-induced liver oxidative injury may occur via the alleviation of oxidative stress and inflammatory response.