Background: Aims: To elucidate the mechanism of SYQ flavonoids in mitigating acute lung injury (ALI). Materials and methods: An integrated approach combined network pharmacology, HPLC, lipopolysaccharide (LPS)-induced ALI mouse models, and NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-activated cellular assays (LPS + nigericin). NLRP3 knockdown (siRNA) and molecular docking were employed for mechanistic validation. Results: Network pharmacology and HPLC identified procyanidin B1 and catechin as core active compounds targeting the NLRP3 inflammasome pathway. Animal experiments demonstrated that SYQ flavonoids can significantly alleviate pathological damage to lung tissue, reduce pulmonary edema, and inhibit the expression of pro-inflammatory factors, thereby exerting a protective effect against ALI. Furthermore, SYQ flavonoids exhibited protective effects against ALI by downregulating the expressions of interleukin (IL)-1β, IL-18, NLRP3, ASC, and caspase-1. Notably, when NLRP3 was knocked down using siRNA technology, it had no significant effect on the levels of IL-1β and IL-18, indicating that their therapeutic effects are mediated through the NLRP3 pathway. Finally, molecular docking confirmed that both catechin and procyanidin B1 exhibit strong binding affinities with NLRP3, providing a molecular basis for their targeted inhibition of the NLRP3 inflammasome. Conclusion: SYQ flavonoids alleviate ALI by specifically inhibiting the NLRP3 inflammasome, providing a mechanistic basis for its traditional use in lung inflammation.