Splenectomy is a common surgical procedure performed in millions of people worldwide. Epidemiologic data show that splenectomy is followed by infectious (sepsis) and non‐infectious complications, with unknown mechanisms. In order to explore the role of the non‐coding transcripts involved in these complications, we analysed a panel of circulating microRNAs (miRNAs), which were previously reported to be deregulated in sepsis, in the plasma of splenectomized patients. MiR‐223 was overexpressed immediately and late after splenectomy, while miR‐146a was overexpressed immediately after splenectomy, returning latter to basal levels; and miR‐16, miR‐93, miR‐26a and miR‐26b were overexpressed only late after splenectomy, suggesting similarities with sepsis. We also explored the non‐coding (nc)RNome of circulating peripheral blood leucocytes by performing a ncRNA full genome profiling. We observed a reorganization of the ncRNoma after splenectomy, characterized by up‐regulation of miRNAs and down‐regulation of transcribed pyknons (T‐PYKs). Pathway analysis revealed that deregulated miRNAs control pathways involved in immunity, cancer and endothelial growth. We checked the expression of the ncRNAs in 15 immune cell types from healthy donors and observed that plasma miRNAs, cellular miRNAs and T‐PYKs have a cell‐specific expression pattern and are abundant in different types of immune cells. These findings suggest that the ncRNAs potentially regulate the immune changes observed after splenectomy.