Antimicrobial resistance (AMR) of bacteria has increased worldwide dramatically and the development of new antibiotics has been slowed down. Therefore, it is urgent to explore new anti-infective drugs or therapeutics. Quorum sensing (QS) system of pathogen is closely related to its pathogenicity. QS system inhibitors could significantly reduce the pathogenicity of pathogen. QS system is mainly composed of las, rhl, and pqs systems and Sargentodoxae Caulis extracts mainly containing caffeic acid which has shown QSI activity. In this study, we proved the antivirulence and antipathogenicity of caffeic acid against Pseudomonas aeruginosa at the transcript and product level, then we further investigate the target of caffeic acid in QS system by using molecular docking combining the mutant strains determination. The results indicated that caffeic acid could reduce the expression of QS-related genes rhlR, rhlI, pqsA, pqsR as well as virulence related genes such as phzA 1、lasB. Motility ability and biofilm were also suppressed obviously by caffeic acid. Chinese cabbage and fruit fly infection model analysis verified the antipathogenicity of caffeic acid. Caffeic acid might inhibit QS system by targeting the pqs system based on the docking analysis and gene mutant strains evaluation on caffeic acid.