The invention provides a preparation method of carboxyl terminated polyethylene glycol modified mesoporous silica nano particles. The preparation method includes: dissolving double-end carboxyl terminated polyethylene glycol (HOOC-PEG-COOH) into water, adding 1-ethyl-(3-dimethyl amino propyl) carbodiimide hydrochloride (EDC.HCL), stirring for 10-15 minutes, adding N-hydroxysuccinimide (NHS) to perform reaction and activation for 0.5-1 hour, dropwise slowly adding amino modified mesoporous silica nano particles (CMS-NH2) to perform reaction under room temperature for 4-12 hours, centrifuging, washing with distilled water for 3-5 times, and dispersing in water for preservation to obtain the carboxyl terminated polyethylene glycol modified mesoporous silica nano particles CMS-PEG-COOH. The preparation method has the advantages that the double-end carboxyl terminated polyethylene glycol is used for modifying the surfaces of the mesoporous silica nano particles through amido bonds to increase the colloidal stability of the nano particles; carboxyl functional groups contained in the tail ends of the modified nano particles can be combined with many targeting molecules to achieve the targeting conveying of drugs.