Background: This study used bioinformatics combined with statistical methods to identify plasma biomarkers that can predict intracranial aneurysm (IA) rupture and provide a strong theoretical basis for the search for new IA rupture prevention methods. Methods: We downloaded gene expression profiles in the GSE36791 and GSE122897 datasets from the Gene Expression Omnibus (GEO) database. Data were normalized using the “sva” R package and differentially expressed genes (DEGs) were identified using the “limma” R package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used for DEG function analysis. Univariate logistic regression analysis, least absolute shrinkage and selection operator (LASSO) regression modeling, and the support vector machine recursive feature elimination (SVM-RFE) algorithm were used to identify key biomarker genes. Data from GSE122897 and GSE13353 were extracted to verify our findings. Results: Eight co-DEG mRNAs were identified in the GSE36791 and GSE122897 datasets. Genes associated with inflammatory responses were clustered in the co-DEG mRNAs in IAs. CD6 and C-C chemokine receptor 7 (CCR7) were identified as key genes associated with IA. CD6 and CCR7 were upregulated in patients with IA and their expression levels were positively correlated. There were significant differences in the infiltration of immune cells between IAs and normal vascular wall tissues (p 0.05). A predictive nomogram was designed using this two-gene signature. Binary transformation of CD6 and CCR7 was performed according to the cut-off value to construct the receiver-operating characteristic (ROC) curve and showed a strong predictive ability of the CD6-CCR7 gene signature (p 0.01; area under the curve (AUC): 0.90; 95% confidence interval (CI): 0.88–0.92). Furthermore, validation of this two-gene signature using the GSE122897 and GSE13353 datasets proved it to be valuable for clinical application. Conclusions: The identified two-gene signature (CD6-CCR7) for evaluating the risk of IA rupture demonstrated good clinical application value.