Methotrexate intercalated Mg-Al layered double hydroxide composites (MTX-LDH) were prepared via combination of coprecipitation and hydrothermal synthesis by using Mg(NO3)2•6H2O and Al(NO3)3•9H2O as main materials. The effects of main technological conditions on drug loading rate, particle size and dispersion of MTX-LDH composite were analyzed by orthogonal test. The results showed that the composites had good monodispersity, suitable particle size (175.6nm), and high drug loading rate (18.9%) when the reaction temperature was 60℃, and the amount of Mg(NO3)2•6H2O, Al(NO3)3•9H2O, MTX and polyethylene glycol 400 were 2.67 mmol, 1.33 mmol, 0.2 mmol and 15 mL respectively. The structure, thermodynamic properties and micro-morphology of the samples were studied by FTIR, XRD, TG and TEM. The release properties of MTX-LDH composite particles in different pH buffer solutions were investigated emphatically. It was indicated that the composites had the characteristics of pH-responsive release and good sustained release properties in weak acid environment with pH=5.8, and the cumulative release rate at 12 h was up to 93.7%. Moreover, the release mechanism of laminate dissolution coexist with displacement diffusion was confirmed by the thermodynamic release model.