A high-efficacy, long-acting formulation of silibinin, comprising silibinin solid dispersion, silibinin-loaded silica nanoparticles, slow-release matrix material and release enhancer, wherein the mass ratio of these components is silibinin solid dispersion:silibinin-loaded silica nanoparticles:slow-release matrix material:release enhancer=1:0.5˜1.25:0.1˜0.3:0.1˜0.3; the drug loading rate of the said silibinin-loaded silica nanoparticles is 51.29˜51.77%; the said silibinin solid dispersion contains povidone K30, soybean lecithin, acrylic resin IV, wherein the mass ratio between silibinin and other medical accessories is silibinin:povidone K30:soybean lecithin:acrylic resin IV=1:1˜3:0.3˜0.8:0.2˜0.5. Compared with the existing formulations, the half life of the high-efficacy, long-acting formulation of silibinin disclosed in this invention is 14.8 times longer while the mean residence time (MRT) of which is 4.52 times longer; when tested in vivo in Beagle dogs, this new formulation of silibinin presents a smoother concentration-time curve and reaches the continuous release for 72 hours. This invention discloses its preparation method.