Luteolin is a natural flavonoid that has a variety of pharmacological activities, such as anti-inflammatory, anti-allergic, anti-bacterial, antiviral, apoptosis inhibition, cell autophagy regulation, and anti-tumor activity. It is one of the main ingredients of an expert-recommended herbal formula for the prevention and treatment of coronavirus disease 2019 (COVID-19). This suggests that luteolin has strong pharmacological effects on the prevention and treatment of COVID-19. The aims of this study were to identify the molecular targets of luteolin and to infer the possible mechanisms by which it exerts its pharmacological effects. The GSE159787 data set was obtained from the Gene Expression Omnibus online database, and differentially expressed genes were analyzed. There were 22 upregulated differentially expressed genes enriched in the COVID-19 signaling pathway, suggesting that the upregulation of these genes may be closely related to the occurrence of COVID-19. Molecular docking results showed that luteolin had strong binding efficiency to 20 of these 22 key genes. Six of these genes (CFB, EIF2AK2, OAS1, MAPK11, OAS3, and STAT1) showed strong binding activity. Luteolin can regulate the COVID-19 signaling pathway by combining with these targets, which may have a therapeutic effect on COVID-19.