With the rapid development of nanotechnology, mesoporous silica nanoparticles (MSNs) with numerous forms and structures have been synthesized and extensively applied in biomedicine in the past decades. However, our knowledge about the biocompatibility of the developed MSNs has not matched their development. Therefore, in this work, we have synthesized sphere-shaped MSNs with different pore scales (s-SPs and l-SPs) and rod-shape (RPs-3) MSNs to evaluate the influence of the morphology and pore size on their interaction with serum proteins and red blood cells (RBCs). The adsorption of human albumin (HSA), globulin (HGG), and fibrinogen (HSF) onto different kinds of MSNs has been analyzed by pseudo second-order kinetic model, and the conformational changes of the adsorbed proteins have been studied by FTIR spectroscopy. We find that the conformation of absorbed HSA and HSF, while not HGG, will be affected by the pore size and morphology of the MSNs. The conformational changes of the adsorbed proteins will further affect their saturated adsorption capacity. However, the initial adsorption rate is only determined by the property of MSNs and proteins. Additional hemolysis assay shows that the pore size and morphology of the MSNs will also affect their hemolytic activity in RBCs which will be extremely depressed by the formation of protein corona. These systematic studies will provide an overall understanding in the blood compatibility of MSNs as well as useful guidelines for fabrication of blood-compatible nanomaterials.