This paper presents a performance comparison of heterostructure surface plasmon resonance (SPR) biosensors for the application of Novel Coronavirus SARS-CoV-2 diagnosis. The comparison is performed and compared with the existing literature based on the performance parameters in terms of several prisms such as BaF
2
, BK
7
, CaF
2
, CsF, SF
6
, and SiO
2
, several adhesion layers such as TiO
2
, Chromium, plasmonic metals such as Ag, Au, and two-dimensional (2D) transition metal dichalcogenides materials such as BP, Graphene, PtSe
2
MoS
2
, MoSe
2
, WS
2
, WSe
2
. To study the performance of the heterostructure SPR sensor, the transfer matrix method is applied, and to analyses, the electric field intensity near the graphene-sensing layer contact, the finite-difference time-domain approach is utilized. Numerical results show that the heterostructure comprised of CaF
2
/TiO
2
/Ag/BP/Graphene/Sensing-layer has the best sensitivity and detection accuracy. The proposed sensor has an angle shift sensitivity of 390°/refractive index unit (RIU). Furthermore, the sensor achieved a detection accuracy of 0.464, a quality factor of 92.86/RIU, a figure of merit of 87.95, and a combined sensitive factor of 85.28. Furthermore, varied concentrations (0–1000 nM) of biomolecule binding interactions between ligands and analytes have been observed for the prospects of diagnosis of the SARS-CoV-2 virus. Results demonstrate that the proposed sensor is well suited for real-time and label-free detection particularly SARS-CoV-2 virus detection.