Quick hemostasis plays a very important role in preventing hemorrhagic shock and death by controlling blood loss from trauma in civil and military accidents. An ideal quick hemostat should have tissue-adhesive functional groups, clotting factor activating components, and a plasma non-permeable hydrophobic layer. Inspired by the adhesive behavior of mussels, a novel efficient hemostat of urushiol-functionalized mesoporous silica nanoparticles (MSN@U) with a core–shell structure was synthesized and their hemostatic performance was evaluated for the first time. MSN@U could form an amphipathic Janus membrane (a hydrophobic layer and a hydrophilic layer in one membrane) by interfacial self-assembly. The morphology and structure of MSN@U were characterized. The results showed that MSN@U possessed a large specific surface area of 448.91 m² g⁻¹ and a rich porous structure with an average pore diameter of 3.94 nm. The hydrophilic catechol groups and the long hydrophobic alkyl groups of urushiol allowed MSN@U to self-assemble at the blood/air interface. The former made MSN@U tightly adhere onto blood vessel tissue through covalent bonds, while the latter formed a hydrophobic barrier layer which hindered blood from oozing. Meanwhile, MSN@U would accelerate clotting cascade reactions. These three effects made MSN@U a very quick hemostat with a hemostatic time of 22 ± 2 s on a rat liver laceration. Both in vitro and in vivo tests showed that they had a better hemostatic effect and blood compatibility than MSN. Cell viability evaluations indicated that MSN@U had no cytotoxicity. MSN@U will be a safe and promising hemostatic agent for clinical applications.