Since December 2019, Coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant morbidity and mortality worldwide. There is an increased risk of ischemic stroke (IS) associated with COVID-19. However, few studies have been reported to explain the potential correlation between COVID-19 and IS. We investigated the relationship and relevant mechanisms between COVID-19 and IS using single-cell RNA sequencing and multiple bioinformatics approaches. By intersecting differentially expressed genes and WGCNA critical module genes, we obtained 73 COVID-19-related IS genes. According to the KEGG pathway analysis, the COVID-19-related IS disease genes were significantly enriched in the hematopoietic cell lineage pathway, ribosome pathway, COVID-19 pathway and primary immunodeficiency pathway. Finally, three genes associated with immunity (B4GALT5, CRISPLD2, F5) and two genes associated with ferroptosis (ACSL1, CREB5) were identified up-regulated in COVID-19-related IS. Significantly, it was found that all five genes were highly expressed in monocytes by single cell RNA sequencing. We believe these genes (B4GALT5, CRISPLD2, F5, ACSL1, CREB5) may regulate the immune response and ferroptosis of multiple immune cells, mainly including monocytes, which may contribute to the development of COVID-19-related IS. In addition, these genes may be potential targets for the treatment of COVID-19-related IS.