Non-small cell lung cancer (NSCLC) is a common subtype of lung cancer that has received considerable attention for its potential association with rheumatoid arthritis (RA). However, current understanding of the relationship between RA and NSCLC risk remains limited and in-depth studies of molecular mechanisms are lacking.We obtained transcriptomic data of NSCLC from the Gene Expression Omnibus (GEO) database and performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of differential genes. We then used Mendelian randomisation (MR) analysis to explore the causal relationship between RA and NSCLC, but the results showed no direct causal relationship between RA and NSCLC. In light of this finding, we shifted our research focus to investigate the effect of RA therapeutics on NSCLC risk. A drug-targeted MR analysis of drugs available for the treatment of RA was performed by searching for drugs that target NSCLC differential genes associated with RA.We found that several of the drugs corresponding to NSCLC differential genes associated with RA are used to treat RA. By drug-targeted MR analysis of drugs, we found that some drugs do have an effect on the risk of developing NSCLC, increasing the risk of developing NSCLC.This study employed transcriptomic analysis and MR of drug targets to elucidate the potential correlation between RA and the risk of developing NSCLC. The identification of NSCLC differentially expressed genes associated with RA and their drug targets has provided new perspectives for an in-depth understanding of the pathogenesis of NSCLC. Furthermore, an additional immune infiltration analysis demonstrated that, in NSCLC tissues, the infiltration levels of specific immune cell subpopulations, including regulatory T cells (Tregs), activated natural killer cells (NK cells) and unpolarised macrophages (M0), exhibited notable differences. These findings emphasise the significant role that immune cell interactions between RA and NSCLC may play in disease progression. Furthermore, through the analysis of validation histology, we have further confirmed the potential role of differential genes associated with RA in the development of NSCLC. The expression levels of these genes demonstrated significant differences in NSCLC samples, providing a basis for possible future therapeutic targets and biomarkers.© 2025. The Author(s).