Abstract: This paper systematically summarizes the latest progress in research of blood biomarkers of Creutzfeldt-Jakob disease (CJD). The existing blood biomarkers are categorized into five classes: scrapie prion protein (PrP^Sc), neuronal injury markers, exosomal nucleic acids, epigenetic signatures, and metabolic markers. The performance, advantages, and limitations of the detection techniques for each category of biomarkers are compared. The blood biomarkers, especially the key indicators such as PrP^Sc, neurofilament light chain, and total tau protein, show great potential for the non-invasive diagnosis, early screening, and disease monitoring of CJD, the combined use of the biomarkers can further enhance their efficacy. Currently, the integration of multi-omics data and the development of novel detection platforms are driving the field from single-marker analysis toward comprehensive assessment. Overall, blood biomarker detection are expected to revolutionize the traditional invasive diagnostic paradigm for CJD. Future research should focus on technological standardization, multi-center validation, and clinical translation to facilitate the precise medicine in prion disease diagnosis.