Silibinin is effective in significantly inhibiting the growth of cancer cells which shown significant anti-neoplastic effects in a variety of in vitro and in vivo cancer models, including skin, breast, lung, colon, bladder, prostate and kidney carcinomas. So, development of a new method to its biomedical analysis in clinical samples in highly demanded. In this study, an innovative electroanalysis method for the accurate, sensitive and rapid recognition of silibinin in human plasma samples was proposed and validated. The sensing platform was designed using silver nanoparticles (AgNPs) dispersed on the polymeric layer of β-cyclodextrin (β-CD). AgNPs with cubic shape providing a large effective surface area for β-CD electropolymerization. So, a layer with high electron conductivity boosting the detection electrochemical signals. Also, poly(β-CD) providing an efficient substrate with cavities to interact with silibinin and its oxidation. Differential pulse voltammetry technique was conducted to measure silibinin concentration in human real samples. Under optimized conditions, proposed sensor indicated linear relationship between the anodic peak current and concentration of silibinin in the range of 0.0103–10.3 µM on the standard and human plasma samples. Based on obtained results, proposed sensor is an efficient platform to efficient therapy of cancer based on recognition of silibinin in clinical samples.