The study identifies the low-density lipoprotein receptor (LDLR) as the entry receptor for Crimean-Congo hemorrhagic fever virus (CCHFV), a severe tick-borne zoonotic bunyavirus. Genetic knockout of LDLR impairs CCHFV infection in various susceptible human, monkey, and mouse cells, which is restored by reconstitution with ectopically expressed LDLR. Mutagenesis studies indicate that the ligand binding domain (LBD) of LDLR is essential for CCHFV infection. LDLR binds directly to CCHFV glycoprotein Gc with high affinity, supporting virus attachment and internalization into host cells. 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 a critical entry receptor for CCHFV, and pharmacological targeting of LDLR may provide a strategy to prevent and treat Crimean-Congo hemorrhagic fever.The study identifies the low-density lipoprotein receptor (LDLR) as the entry receptor for Crimean-Congo hemorrhagic fever virus (CCHFV), a severe tick-borne zoonotic bunyavirus. Genetic knockout of LDLR impairs CCHFV infection in various susceptible human, monkey, and mouse cells, which is restored by reconstitution with ectopically expressed LDLR. Mutagenesis studies indicate that the ligand binding domain (LBD) of LDLR is essential for CCHFV infection. LDLR binds directly to CCHFV glycoprotein Gc with high affinity, supporting virus attachment and internalization into host cells. 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 a critical entry receptor for CCHFV, and pharmacological targeting of LDLR may provide a strategy to prevent and treat Crimean-Congo hemorrhagic fever.