Background: Hepatitis B virus (HBV) infection is a serious worldwide health concern, especially in highly endemic areas like Egypt. Prolonged HBV infection causes serious liver problems that need efficient antiviral treatment. Although nucleoside analogs are often utilized in medicine, patient response differs for a variety of reasons. Improving outcomes requires an understanding of the molecular processes driving therapy response. Nuclear factor erythroid 2-related factor 2 (NrF2) and matrix metalloproteinase-9 (MMP-9) have been identified as important regulators of HBV pathogenesis and antiviral treatment response. Methods: In this outpatient clinic case-control research, 102 controls and 428 HBV patients participated. PCR was used to evaluate the genetic expression of NrF2 and MMP-9. Gene expression levels were used to assess therapy response in patients receiving nucleoside analogues. Results: Patients receiving various nucleoside analogues showed significant variations in MMP-9 and NrF2 expression. When compared to naïve or control groups, entecavir medication was linked to a substantial decrease in MMP-9 expression, indicating that it is effective in lowering MMP-9 levels. Comparatively speaking to MMP-9, NrF2 expression showed rather similar tendencies. Conclusion: our research sheds light on the molecular processes that underlie Egyptian HBV patients' responses to nucleoside analogue therapy via the MMP-9 and NrF2 pathways. In cases of chronic HBV infection, MMP-9 and NrF2 show potential as prognostic biomarkers for treatment outcomes. To further understand processes and investigate clinical consequences, more research is required. This might lead to the development of tailored treatment strategies that improve clinical results.