Dry eye disease seriously affects people’s work and life. Chufeng Yisun Decoction is a traditional Chinese medicine decoction used in treating dry eye disease. This study aims to explore the core active ingredients, targets, and mechanisms of CFYSD in dry eye disease, providing new insights for the dry eye disease treatment.

A total of 196 target genes were screened from Chufeng Yisun Decoction and 170 genes were related to dry eye disease. Gene Ontology and KEGG enrichment analysis showed that Chufeng Yisun Decoction influenced dry eye disease through “Lipid and atherosclerosis”, “Fluid shear stress and atherosclerosis” and “PI3K-Akt”. The core targets of Chufeng Yisun Decoction in treating dry eye disease were Akt1 and IL-1β. The core active ingredients were kaempferol, wogonin, and quercetin. Molecular docking results showed that the binding energies of kaempferol and Akt1, wogonin and Akt1, quercetin and Akt1, and quercetin and IL-1β were -6.1, -6.1, -6.1, and -7.9 kcal/mol, respectively. Chufeng Yisun Decoction significantly alleviated cell damage and reduced PI3K/Akt pathway-related protein expression. PI3K activation partially reversed the therapeutic effect of Chufeng Yisun Decoction on dry eye disease.