Background: Lung adenocarcinoma (LUAD), which is the most common lung cancer type in never-smokers and primarily occurs in women, requires effective treatment methods. Mangiferin is a polyphenol widely found in mango trees and has been reported to have chemotherapeutic and preventive potential against various types of cancer. Thus, we investigated the potential therapeutic value of mangiferin for LUAD.Methods: Cell lines A549, H2030 and H1299 were processed with mangiferin to detect and screen for differentially expressed lncRNAs and mRNAs. Close associations between extracted common lncRNAs and mRNAs were identified for lncRNA-mRNA network construction. Based on the network and an online database, target lncRNAs, target genes and meaningful lncRNA-mRNA pairs were identified, and signaling pathway analysis was performed.Results: The top 200 lncRNA-mRNA pairs were used to construct the network. We identified 12 target lncRNAs and 18 target genes. Gene nodes in the network were mostly visualized on the PI3K-Akt signaling pathway (P < 0.01). Furthermore, lncRNA-mRNA pairs that contained the genes ARHGAP29, BRIX1, CD109, CDK1, CTNNAL1, DAB2IP, DDIT4L, GPR162, ICAM5, KCNAB3 and MMP7 were considered to be meaningful lncRNA-mRNA pairs affected by mangiferin in LUAD.Conclusions: Our study provided a comprehensive understanding of the potential therapeutic value of mangiferin for LUAD.