The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2), has led to a global crisis that included collapsing healthcare systems and shut-down communities, producing considerable economic burden . Despite the number of effective vaccines quickly implemented, the emergence of new variants is a primary concern . The scientific community undertook a rapid response to better study this new virus . However, critical questions about viral protein-protein interactions and mechanisms of its physiopathology are still unclear . Although severe COVID-19 was associated with hematological dysfunctions, scarce experimental data were produced about iron dysmetabolism and the viral proteins ’ possible interaction with hemoglobin (Hb) chains . This work demonstrates the binding of SARS-CoV-2 proteins to hemin and Hb using a multimethodological approach . In silico analysis indicated binding motifs between a cavity in the viral nucleoprotein and hemoglobin ’ s porphyrin coordination region . Different hemin binding capacities of mock and SARS-CoV-2-infected culture extracts were noticed using gel electrophoresis and TMB staining . Hemin-binding proteins were isolated from SARS-CoV-2-infected cells by affinity chromatography and identified by shotgun proteomics, indicating that structural (nucleoprotein, spike, and membrane protein) and non-structural (Nsp3 and Nsp7) viral proteins interact with hemin . In vitro analyses of virus adsorption to host cells and viral replication studies in Vero cells demonstrated inhibitory activities - at different levels - by hemin, protoporphyrin IX (PpIX) Hb . Strikingly, free Hb at 1μM suppressed viral replication (99 %), and its interaction with SARS-CoV-2 was localized to the RBD region of the Spike protein . The findings showed clear evidence of new avenues to disrupt viral replication and understand virus physiopathology that warrants further investigation.