Quetiapine fumarate (QF) is an antipsychotic drug that has been most widely prescribed as an antipsychotic. In this regard, sensitive recognition of QF in bodily fluids must be done accurately. In this work, an electrochemical sensor for QF detection was fabricated, using GNSs‐PDA@SiO₂ modified rGO stabilized on glassy carbon electrode. According to the electrical nature of gold nanoparticles (GNPs), polydopamine (PDA), and its composition with nano‐silica, the proposed hybrid material is able to enhance the electro‐oxidation signals of QF toward its sensitive detection in complex biological media. The morphology of synthesized polymeric nanocomposites and various surfaces of electrodes were investigated using Field Emission Scanning Electron Microscopy and Energy‐Dispersive X‐Ray Spectroscopy methods. Using the square wave voltammetry technique, the fabricated electrochemical sensor could detect QF in the linear range of 500 μM to 3 mM, which low limit of quantification was obtained as 500 μM, indicating the sensor's appropriate sensitivity. For the first time, the application of novel hybrid material (GNSs‐PDA@SiO₂) for pharmaceutical analysis in human plasma was studied using electrochemical sensor technology. Based on the obtained analytical results, engineered nano‐surface led to entrapment and oxidation of QF in real samples. So, a novel and efficient method for the analysis of QF was designed and validated, which opens a new horizon for pharmaceutical analysis and therapeutic drug monitoring.