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Surface-enhanced Raman spectroscopy (SERS) has emerged as a highly promising analytical technique for disease diagnostics due to its exceptional sensitivity, molecular specificity, and ability to detect a broad range of biomarkers in complex biological matrices. This review provides a comprehensive overview of gold- and silver-nanoparticle-based SERS platforms for plasma disease diagnostics, covering advances in plasmonic nanostructures, biological sample analysis, biomarker detection, and AI-driven spectral data processing. Particular emphasis is placed on the application of SERS to clinically relevant biofluids, especially plasma, where the technique has demonstrated considerable potential for detecting diseases such as cancer, inflammatory disorders, and neurological conditions. The review also critically examines the major challenges currently limiting the clinical translation of SERS technologies. These include variability associated with substrate fabrication, matrix-induced signal fluctuations, limited interlaboratory reproducibility, and the lack of standardized protocols for spectral preprocessing and data analysis. Strategies proposed to address these issues are discussed, including comprehensive post-synthesis substrate characterization, optimization of biological sample preparation, advanced spectral preprocessing workflows, and the integration of machine learning and artificial intelligence algorithms to improve diagnostic robustness and reproducibility. Collectively, the advances summarized in this review indicate that SERS-based diagnostic technologies are rapidly progressing beyond proof-of-concept studies toward clinically applicable systems. Continued interdisciplinary collaboration and standardization efforts will be essential to bridge the remaining gap between experimental SERS methodologies and routine clinical implementation.