Hepatocellular carcinoma (HCC) is the most common type of liver cancer and a leading cause of cancer-related deaths worldwide. While early detection significantly improves prognosis, patients with alpha-fetoprotein-negative hepatocellular carcinoma (ANHCC) often face diagnostic challenges due to the lack of reliable biomarkers. This review systematically explores the potential of various circulating biomarkers in the early diagnosis of ANHCC, including AFP-L3, PIVKA-Ⅱ, lymphocyte-to-monocyte ratio, exosomes, circulating cell-free DNA (cfDNA), circulating tumor cells, osteopontin, paraoxonase 1, autoantibodies, and RNA-related biomarkers. The combined use of these markers, particularly AFP-L3 and PIVKA-Ⅱ, demonstrates enhanced diagnostic accuracy and specificity compared to single markers. Emerging evidence also highlights the diagnostic potential of exosomes, cfDNA, and RNA markers due to their non-invasive nature and high stability. Despite promising results, further large-scale, multicenter studies are needed to validate these findings, address challenges such as standardization of detection methods, and elucidate underlying mechanisms. These advances are anticipated to significantly improve early detection and personalized management of ANHCC.