Nano-materials are highly exploited to enhance sensing performance of electrochemical electrodes by increasing the Electro-Active Surface Area (EASA). In this work, an analytical calculation of the deposited EASA is presented and experimentally validated by comparing two kinds of nanostructured electrochemical sensors modified with Multi-Walled Carbon Nano-Tubes (MWCNTs) and fullerenes. Further, the two differently nano-structured electrodes, prepared with equal optimum EASA, have been adopted as novel approach in the detection of Paracetamol (APAP) and Midazolam (MZ), two largely adopted and complementary sedative drugs. We have used the novel approach to let emerge the different nano-scale structures’ sensing performance at the same equivalent EASA. The analytical method for EASA calculation has been recently validated by our group on different nano-materials; hence the aim of the actual work is to present, for the first time, its efficient applicability also in comparing the performance of different allotropes of the same nature (carbon-based) in drug sensing, e.g. MZ and APAPA. Our study also includes the comparison in undiluted Human Serum (HS), proposed here as complex biosample, to confirm the validity of our novel approach close to real applications. With respect to Fullerenes, the MWCNTs-modified electrodes obtained the best LOD values in HS detection, as 0.3518 μM and 0.5367 mM for APAP and MZ, respectively. Scanning Electron Microscopy (SEM) analysis also confirmed the higher quality of MWCNTs-based surface in terms of homogeneity and denser coverage of the surface with respect to fullerene-based one, with a better-packed aggregate of assembled structures.