An innovative paper-based electrochemical aptasensor has been developed for the detection of Rivaroxaban (RIV) in human plasma samples. The sensor is fabricated using a novel prob by encapsulating aptamer-aminated on dendritic fibrous nano-silica (KCC-1-NH-CS2) particles. The prob is then immobilized on the functionalized silver nano-ink electrode.. The resulting redox reaction on the prob was subsequently evaluated using square wave voltammetry, differential pulse voltammetry, and chronoamperometry. Under optimized condition and using a label-free strategy, the aptasensor exhibited suitable sensitivity and specificity for detecting RIV with a linear range of 10 to 1000 nM and a lower limit of quantification (LLOQ) of 10 nM. The engineered aptasensing platform shows great potential for the fabrication of other cost-effective, sensitive, and portable biosensors for the pharmaceutical and biomedical analysis.