<p>Sporadic Creutzfeldt–Jakob disease (sCJD) is the most prevalent human prion disease, characterized by rapidly progressive neurodegeneration and an invariably fatal outcome. This review comprehensively examines the epidemiological features, molecular pathogenesis, clinical manifestations, diagnostic approaches—including neuroimaging, laboratory assays, cerebrospinal fluid analysis, and genotyping—and current therapeutic strategies alongside prognosis evaluation of sCJD. Despite advances in understanding prion biology and disease mechanisms, challenges remain in early diagnosis and effective treatment. Recent progress in biomarker discovery, refinement of diagnostic criteria, and emerging therapeutic interventions is highlighted to provide an integrated perspective on sCJD management. By synthesizing the latest research findings, this article aims to offer a thorough reference for clinicians and researchers, facilitating improved diagnostic accuracy and patient care, and guiding future investigations into this fatal neurodegenerative disorder.</p>