Chlorogenic acid (CGA), a phenolic compound widely distributed in plants, has exhibited inhibitory activity against Helicobacter pylori ( H. pylori ) by effectively suppressing urease, a key virulence factor of the pathogen. This study aimed to investigate the binding affinity between CGA and urease and explore the underlying molecular mechanism. Inhibition kinetics were characterized using Lineweaver–Burk plots, fluorescence quenching, isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR). The binding mode was elucidated using molecular docking and molecular dynamics simulations. The results demonstrated that CGA exhibited a mixed‐type inhibition against H. pylori urease (HPU). CGA quenched the intrinsic fluorescence of HPU via a static quenching mechanism, with the quenching constant ( K _q ) of 0.41 ± 0.04 × 10 ¹³ M ⁻¹ s ⁻¹ . The thermodynamic parameters indicated that the interaction between CGA and HPU was exothermic and enthalpy‐driven (Δ G < 0, Δ H < 0). SPR data revealed that CGA had a dissociation constant ( K _D ) of 1.63 ± 0.19 × 10 ⁻⁵ M. CGA bound to HPU near the active site and flap region, forming a stable complex. These findings contribute to the understanding of phenolics in anti‐ H. pylori therapy and highlight CGA as a promising lead compound for the development of innovative urease‐targeted applications.