Hepatitis B is an infectious disease of great public health importance. Nigeria is one of the countries with the highest incidence of Hepatitis B Virus (HBV) infection worldwide. However, the accessibility and affordability of HBV DNA quantification (viral load) assay is the key laboratory test for therapy initiation, and monitoring is a challenge to HBV management. This study aimed at determining the relationship between HBV DNA quantification and routine haemato-serological parameters in order to develop a more cost-effective diagnostic algorithm for Hepatitis B management. Cross sectional study design was used with a total of 264 subjects comprising of 88 HBsAg seropositive treatment naïve subjects, 88 HBsAg seropositive subjects on antiviral therapy as case subjects and 88 age-matched apparently healthy HBsAg seronegative individuals were recruited as control subjects. Hepatitis B Virus DNA assay was performed using real time PCR technique while ELISA technique was used for Hepatitis B surface antigen quantification. HBsAg quantification showed strong positive correlation with HBV DNA viral load both in treatment and non-treatment groups (r = 0.673; p < 0.001). However, the Receiver Operation Characteristics curve indicated a very poor performance characteristics (AUC = 0.537, p = 0.002). The non-treatment group has higher viral load (M = 805.50 IU/ml) compared with treatment group (M = 65.50 IU/ml) (p < 0.001). There was a significant difference in HBV DNA levels among the four serological patterns observed in the study (p < 0.001). This study has revealed that HBsAg quantification has strong correlation with HBV viral load but might not be efficient in clinical practice as a predictor of serum HBV viral load due to its poor performance characteristics in identifying high positive viral load.