A simple drug controlled delivery system is facilely designed for pH‐responsive delivery of methotrexate (MTX), an anticancer drug. Aminated mesoporous silica nanoparticles (AMSNs) were first synthesized for the loading of MTX, and then the MTX‐loaded AMSN (AMSN‐MTX) was encapsulated with hyaluronic acid (HA) through electrostatic attractions. Successful preparation of the HA‐encapsulated AMSN‐MTX (AMSN‐MTX‐HA) is confirmed by different characterizations such as scanning electron microscopy, Fourier transform infrared, x‐ray diffraction, and so on. Because the protonation/deprotonation of HA is closely related to pH, the electrostatic interactions between HA and AMSN depend closely on the pH of the medium and thus pH‐responsive delivery of MTX is achieved. The release kinetic data of MTX from the carrier fit well to Higuchi and Korsmeyer‐Peppas models. Cell experiments indicate that the developed AMSN‐MTX‐HA displays high inhibitory effect on hepatoma (SMMC‐7721) cells while the drug‐free carrier of AMSN‐HA has good biocompatibility. [ABSTRACT FROM AUTHOR]