Mild hemolysis of senescent erythrocytes occurs physiologically in the spleen, resulting in hemoglobin (Hb) release, whereas pathologic erythrocyte rupture characterizes several diseases. Iron recycling from Hb and Hb detoxification have been attributed to the sequestration of Hb-haptoglobin complexes by macrophages. However, it remains unclear whether other routes of Hb clearance exist. Here, we identified LSECs as the primary cells responsible for Hb sequestration, a process that involves macropinocytosis and operates independently of the Hb-haptoglobin receptor CD163. We found that LSECs show high iron content and proteomic signatures indicative of adaptation to Hb turnover, hallmarked by high protein levels of HO-1, BLVRB, ferritins, and hepcidin-controlled ferroportin. Erythrocyte transfusion assays further demonstrated that while splenic red pulp macrophages are adept at erytrophagocytosis, liver Kupffer cells and LSECs mainly clear erythrocyte ghosts and Hb, respectively, transported from the spleen via the portal circulation. Moreover, Hb subunits were classified as top-upregulated proteins in LSECs after stressed erythrocyte injection in mice. High-dose Hb injections in mice resulted in transient hepatic iron retention and early activation of the gene encoding HO-1 (Hmox1) in LSECs. This response was associated with the transcriptional induction of the iron-sensing angiokine Bmp6, culminating in hepcidin-mediated transient serum hypoferremia. Injection of Hb and iron citrate elicited distinct transcriptional signatures in LSECs, and the Bmp6 induction was phenocopied by erythrocyte lysis upon phenylhydrazine. Collectively, we propose that LSECs provide a key mechanism for Hb clearance, establishing the spleen-to-liver axis for physiological iron recycling from Hb and contributing to heme detoxification during hemolysis.