In this study, the biosensing capabilities of conventional and hybrid multilayer structures were theoretically examined based on surface plasmon resonance (SPR). The transfer matrix method is adopted to obtain the reflectance spectra of the hybrid multilayer structure in the visible region. In this regard, the considered SPR sensor is configured as, [prism (CaF2)/Al2O3/Ag/Al2O3/2D material/Al2O3/Sensing medium]. Interestingly, many optimization steps were conducted to obtain the highest sensitivity of the new SPR biosensor from the hybrid structure. Firstly, the thickness of an Al2O3layer with a 2D material (Blue P/WS2) is optimized to obtain an upgraded sensitivity of 360° RIU−1. Secondly, the method to find the most appropriate 2D material for the proposed design is investigated to obtain an ultra-high sensitivity. Meanwhile, the inclusion of black phosphorus (BP) increases the sensor's sensitivity to 466° RIU−1. Thus, black phosphorus (BP) was obtained as the most suitable 2D material for the proposed design. In this regard, the proposed hybrid SPR biosensing design may pave the way for further opportunities for the development of various SPR sensors to be utilized in chemical and biomedical engineering fields.