Hepatitis B virus (HBV) infection is one of the major global public health problems, with nearly 887 000 deaths from HBV-associated disease each year. Due to the persistent presence of covalently closed circular DNA (cccDNA) in the nuclei of liver cells, patients infected with HBV are prone to chronic infection, which increases the risk of developing cirrhosis and hepatocellular carcinoma. Therefore, closely monitoring cccDNA levels during the treatment of HBV infection plays an important role in assessing the condition of patients with chronic hepatitis B. In contrast, cccDNA testing requires invasive liver puncture to obtain, which is difficult to be widely performed in the clinical work. Existing studies have shown that serum HBV RNA can reflect the levels of cccDNA in patients. This article provides a review of the advances in the application of serum HBV RNA detection during the antiviral treatment process in patients with chronic hepatitis B.