Despite the indisputable benefits and advancement of science, technology, and civilization, early diagnosis of healthcare is still a challenging field for the scientific fraternity. The detection of biomarkers is a crucial attribute of prognosis and diagnosis of disease. Out of numerous techniques, surface plasmon resonance (SPR) bestows countless benefits, including , label-free, and real-time assessment, etc., which authorizes the analysis of molecular binding occurrences between biotransducers and biomarkers. In addition, SPR with low-molecular-weight biomarkers lacks selectivity and sensitivity, which ultimately affects binding kinetics. This, in turn, leads to the remarkable development and implementation of numerous selectivity and sensitivity enhancement methods. Among the various noticeable strategies, because of selectivity and sensitivity enrichment substrate for SPR biosensors, affinity-based nanoarchitectured biotransducers stand out as being the best substitute. The present review elaborates significant advances made in the research based on affinity biotransducers for diagnosis using SPR biosensors for biomarker sensing. Moreover, most recent trends and challenges in designing and application of nanoarchitectured affinity biotransducer-based SPR biosensors for detecting low-concentration biomarkers have been reviewed comprehensively. This present review may assist the scientific fraternity in designing an ultramodern novel SPR approach based on affinity biotransducers, along with improved selectivity and sensitivity of SPR biosensors for and real-time diagnostic applications.