LDLR is an entry receptor for Crimean-Congo hemorrhagic fever virus (CCHFV). This study identifies LDLR as a critical entry receptor for CCHFV, demonstrating that LDLR is necessary for CCHFV infection in various human, monkey, and mouse cells. Genetic knockout of LDLR significantly impairs CCHFV infection, while reconstitution with ectopically expressed LDLR restores infection. Mutagenesis studies show that the ligand binding domain (LBD) of LDLR is essential for CCHFV infection. LDLR binds directly to the CCHFV glycoprotein Gc with high affinity, supporting virus attachment and internalization. Soluble sLDLR-Fc fusion protein or anti-LDLR blocking antibodies impair CCHFV infection in various susceptible cells. Genetic knockout of LDLR or administration of an LDLR blocking antibody significantly reduces viral loads, pathological effects, and death following CCHFV infection in mice. These findings suggest that LDLR is an entry receptor for CCHFV and that pharmacological targeting of LDLR may provide a strategy to prevent and treat Crimean-Congo hemorrhagic fever. The study also shows that LDLR is required for CCHFV binding to cells and its internalization. LDLR binds directly to Gc of CCHFV, and LDLR-deficient mice exhibit significantly less body weight loss and higher survival rates after CCHFV infection. LDLR is conserved across different species, making it an ideal receptor for CCHFV transmission from intermediate animal hosts to humans. LDLR is expressed in almost all human tissues, which is correlated with the broad tissue tropism of CCHFV. The study also shows that LDLR is not utilized by other bunyaviruses such as RVFV and EBIV for entry. LDLR is a general entry receptor for CCHFV infection from mouse to human, and targeting CCHFV-LDLR interaction may provide effective therapeutic strategies for the treatment of CCHFV infectious diseases.LDLR is an entry receptor for Crimean-Congo hemorrhagic fever virus (CCHFV). This study identifies LDLR as a critical entry receptor for CCHFV, demonstrating that LDLR is necessary for CCHFV infection in various human, monkey, and mouse cells. Genetic knockout of LDLR significantly impairs CCHFV infection, while reconstitution with ectopically expressed LDLR restores infection. Mutagenesis studies show that the ligand binding domain (LBD) of LDLR is essential for CCHFV infection. LDLR binds directly to the CCHFV glycoprotein Gc with high affinity, supporting virus attachment and internalization. Soluble sLDLR-Fc fusion protein or anti-LDLR blocking antibodies impair CCHFV infection in various susceptible cells. Genetic knockout of LDLR or administration of an LDLR blocking antibody significantly reduces viral loads, pathological effects, and death following CCHFV infection in mice. These findings suggest that LDLR is an entry receptor for CCHFV and that pharmacological targeting of LDLR may provide a strategy to prevent and treat Crimean-Congo hemorrhagic fever. The study also shows that LDLR is required for CCHFV binding to cells and its internalization. LDLR binds directly to Gc of CCHFV, and LDLR-deficient mice exhibit significantly less body weight loss and higher survival rates after CCHFV infection. LDLR is conserved across different species, making it an ideal receptor for CCHFV transmission from intermediate animal hosts to humans. LDLR is expressed in almost all human tissues, which is correlated with the broad tissue tropism of CCHFV. The study also shows that LDLR is not utilized by other bunyaviruses such as RVFV and EBIV for entry. LDLR is a general entry receptor for CCHFV infection from mouse to human, and targeting CCHFV-LDLR interaction may provide effective therapeutic strategies for the treatment of CCHFV infectious diseases.