<p>This study presents an SPR-based biosensor designed to effectively detect Mycobacterium tuberculosis, leveraging 2D materials and a Kretschmann configuration, with all analyses and performance evaluations conducted through comprehensive simulation studies. The biosensor utilizes a CaF₂ prism, niobium pentoxide (Nb₂O₅), silver (Ag), ferric oxide (Fe₂O₃), and black phosphorus (BP). The work concentrates on the design and optimization of the SPR structure to obtain an exceptionally high detection sensitivity for mycobacterium tuberculosis (MTB). Strong plasmonic characteristics are provided by the combination of Ag and Fe₂O₃, and sensitivity is greatly increased by the BP-tunable bandgap and improved light–matter interactions. By facilitating surface functionalization and improving chemical stability, Nb₂O₅ makes the sensor reliable for practical uses. The primary modeling approach was the transfer matrix method (TMM) and finite element method (FEM) was employed to verify the simulation results in order to further validate the design. A maximal sensitivity of 622.33 (deg./RIU) was achieved by fine adjusting the thickness of the Nb₂O₅, Ag, Fe₂O₃, and BP layers in order to optimize the sensing structure. The sensor’s impressive QF of 142.02 (RIU⁻¹), high FOM of 140.09, and narrow FWHM of 4.382 (deg.) suggest strong resolution and detection precision. Moreover, the biosensor exhibited a consistent ability to detect refractive index (RI) fluctuations within the biologically pertinent range of 1.343–1.3551. Superior angular sensitivity and improved optical performance are demonstrated by the proposed structure in comparison with existing SPR biosensor configurations. These findings suggest that the proposed SPR sensor could be an effective and rapid tool for point-of-care testing&#xa0;for&#xa0;TB.</p> Graphical Abstract <p></p>