ObjectiveEvidences show that there may be a link between SLE and COVID-19. The purpose of this study is to screen out the diagnostic biomarkers of systemic lupus erythematosus (SLE) with COVID-19 and explore the possible related mechanisms by the bioinformatics approach.MethodsSLE and COVID-19 datasets were extracted separately from the NCBI Gene Expression Omnibus (GEO) database. The limma package inRwas used to obtain the differential genes (DEGs). The protein interaction network information (PPI) and core functional modules were constructed in the STRING database using Cytoscape software. The hub genes were identified by the Cytohubba plugin, and TF-gene together with TF-miRNA regulatory networks were constructedviautilizing the Networkanalyst platform. Subsequently, we generated subject operating characteristic curves (ROC) to verify the diagnostic capabilities of these hub genes to predict the risk of SLE with COVID-19 infection. Finally, a single-sample gene set enrichment (ssGSEA) algorithm was used to analyze immune cell infiltration.ResultsA total of 6 common hub genes (CDC6, PLCG1, KIF15, LCK, CDC25C, andRASGRP1) were identified with high diagnostic validity. These gene functional enrichments were mainly involved in cell cycle, and inflammation-related pathways. Compared to the healthy controls, abnormal infiltration of immune cells was found in SLE and COVID-19, and the proportion of immune cells linked to the 6 hub genes.ConclusionOur research logically identified 6 candidate hub genes that could predict SLE complicated with COVID-19. This work provides a foothold for further study of potential pathogenesis in SLE and COVID-19.