This study presents structural insights into the activation and inhibition of the CXC chemokine receptor 3 (CXCR3), a G-protein-coupled receptor (GPCR) critical for type 1 immunity. The research determines the structures of human CXCR3 complexes activated by chemokine CXCL11, peptidomimetic agonist PS372424, and biaryl-type agonist VUF11222, as well as the inactive CXCR3 bound to noncompetitive antagonist SCH546738. Structural analysis reveals that PS372424 shares a similar orthosteric binding pocket with the N terminus of CXCL11, while VUF11222 binds deeper and activates the receptor in a distinct manner. An allosteric binding site between TM5 and TM6 accommodates SCH546738 in the inactive CXCR3, potentially restraining the receptor at an inactive state by preventing the repacking of TM5 and TM6. The study reveals the binding patterns and pharmacological properties of the four modulators, providing insights into the activation mechanisms of CXCR3 and guiding future drug development. CXCR3 is a class A GPCR that plays a vital role in T cell function, particularly in the activation of CD4+ T helper (Th1) cells and CD8+ cytotoxic lymphocytes. CXCL9, CXCL10, and CXCL11 are interferon-inducible chemokines that activate CXCR3 with varying affinities. The study shows that CXCL11 is more biased for receptor internalization compared to CXCL9 and CXCL10. CXCR3 is involved in immune cell migration, positioning, and inflammatory responses. The study highlights the importance of CXCR3 in various diseases, including infections, autoimmune diseases, transplantation, and cancers. The research provides a detailed understanding of the structural basis of CXCR3 ligand recognition and receptor activation, which is essential for developing new drugs targeting CXCR3. The findings contribute to the broader understanding of GPCR activation mechanisms and may lead to the development of more effective therapeutics for diseases involving CXCR3.This study presents structural insights into the activation and inhibition of the CXC chemokine receptor 3 (CXCR3), a G-protein-coupled receptor (GPCR) critical for type 1 immunity. The research determines the structures of human CXCR3 complexes activated by chemokine CXCL11, peptidomimetic agonist PS372424, and biaryl-type agonist VUF11222, as well as the inactive CXCR3 bound to noncompetitive antagonist SCH546738. Structural analysis reveals that PS372424 shares a similar orthosteric binding pocket with the N terminus of CXCL11, while VUF11222 binds deeper and activates the receptor in a distinct manner. An allosteric binding site between TM5 and TM6 accommodates SCH546738 in the inactive CXCR3, potentially restraining the receptor at an inactive state by preventing the repacking of TM5 and TM6. The study reveals the binding patterns and pharmacological properties of the four modulators, providing insights into the activation mechanisms of CXCR3 and guiding future drug development. CXCR3 is a class A GPCR that plays a vital role in T cell function, particularly in the activation of CD4+ T helper (Th1) cells and CD8+ cytotoxic lymphocytes. CXCL9, CXCL10, and CXCL11 are interferon-inducible chemokines that activate CXCR3 with varying affinities. The study shows that CXCL11 is more biased for receptor internalization compared to CXCL9 and CXCL10. CXCR3 is involved in immune cell migration, positioning, and inflammatory responses. The study highlights the importance of CXCR3 in various diseases, including infections, autoimmune diseases, transplantation, and cancers. The research provides a detailed understanding of the structural basis of CXCR3 ligand recognition and receptor activation, which is essential for developing new drugs targeting CXCR3. The findings contribute to the broader understanding of GPCR activation mechanisms and may lead to the development of more effective therapeutics for diseases involving CXCR3.