Hepatic ischemia/reperfusion injury (IRI) commonly complicates liver transplantation (LT). However, the precise mechanisms underlying hepatic IRI remain incompletely understood. We acquired single-cell RNA sequencing (scRNA-seq) and transcriptome RNA sequencing data of LT patients from the GEO database. Employing scRNA-seq, we delved into the interplay between non-immune and immune cells in hepatic IRI, pinpointing genes exhibiting altered expression patterns. Integrating insights gleaned from scRNA-seq and transcriptome RNA sequencing datasets, we deepened our comprehension of cellular interactions and underlying mechanisms in hepatic IRI. Additionally, we conducted preliminary validation of identified gene expression alterations using immunofluorescence techniques. Using scRNA-seq, we detected significant changes in the populations of liver sinusoidal endothelial cells (LSECs) and monocytes after hepatic ischemia-reperfusion injury (IRI). By integrating scRNA-seq with bulk transcriptome RNA sequencing data, we identified key genes with dysregulated expression in LSECs (ICAM1, SOCS3, NFKBIZ, JUND, TNFRSF12A and HSPA6) and monocytes (SOCS3, JUND, FPR2 and NR4A2). Our analysis of cell communication indicated that the ANXA1-FPR2 axis might be a pivotal signature in mediating interactions between LSECs and monocytes. We then established a mouse model for IRI, and further analyses using flow cytometry and immunofluorescence showed a significant increase in monocyte proportion post-IR (p < 0.01). Consistently, Western Blot also revealed significant upregulation of ANXA1 and FPR2 (p < 0.01). Our study elucidated the cellular interactions and signalling pathways following IRI. The interplay between LSECs and monocytes likely triggers a cascade of events, promoting monocyte infiltration and amplifying inflammatory responses, thus worsening the deleterious effects of IRI.