In today’s world, the use of biosensors occupies a special place in a variety of fields such as agriculture and industry. New biosensor technologies can identify biological compounds accurately and quickly. One of these technologies is the phenomenon of surface plasmon resonance (SPR) in the development of biosensors based on their optical properties, which allow for very sensitive and specific measurements of biomolecules without time delay. Therefore, various nanomaterials have been introduced for the development of SPR biosensors to achieve a high degree of selectivity and sensitivity. The diagnosis of deadly diseases such as cancer depends on the use of nanotechnology. Smart MXene quantum dots (SMQDs), a new class of nanomaterials that are developing at a rapid pace, are perfect for the development of SPR biosensors due to their many advantageous properties. Moreover, SMQDs are two-dimensional (2D) inorganic segments with a limited number of atomic layers that exhibit excellent properties such as high conductivity, plasmonic, and optical properties. Therefore, SMQDs, with their unique properties, are promising contenders for biomedicine, including cancer diagnosis/treatment, biological sensing/imaging, antigen detection, etc. In this review, SPR biosensors based on SMQDs applied in biomedical applications are discussed. To achieve this goal, an introduction to SPR, SPR biosensors, and SMQDs (including their structure, surface functional groups, synthesis, and properties) is given first; then, the fabrication of hybrid nanoparticles (NPs) based on SMQDs and the biomedical applications of SMQDs are discussed. In the next step, SPR biosensors based on SMQDs and advanced 2D SMQDs-based nanobiosensors as ultrasensitive detection tools are presented. This review proposes the use of SMQDs for the improvement of SPR biosensors with high selectivity and sensitivity for biomedical applications.