Background: Despite extensive efforts towards its elimination, Hepatitis B virus (HBV) continues to be a major concern, posing risk of liver cirrhosis and hepatocellular carcinoma (HCC) in those infected. Therefore, there is a need for reliable biomarkers to accurately assess the infection. While liver enzymes remain the standard diagnostic tools, the anti-inflammatory and anti-tumor interleukin-37 (IL-37) has emerged as a potential biomarker. Aims: To assess the relationship between serum IL-37 and liver enzymes in HBV patients. Methods: Liver enzymes were measured by Fujifilm’s dry chemistry system (Fuji Dri-Chem), whereas Enzyme-Linked Immunosorbent Assay (ELISA) was utilized for determination of IL-37 levels. A total of 100 patients (37 females, 63 males; mean age: 42 years) from the Medical City in Baghdad, along with 50 age/sex-matched controls (23 females, 27 males; mean age: 38 years) were enrolled in this study. Results: The study has demonstrated highly significant variation in TSB, GOT, and ALP (P<0.01) between patients and controls. Additionally, Sex-based differences in TSB and GOT also showed a significant variation (P<0.01), and the diagnostic value was confirmed by receiver operating characteristic (ROC) curve analysis. Furthermore, a high significant divergence in IL-37 levels was observed between patients and controls [P<0.01, IQR: 32.4 vs. 61.4 Picogram/Milliliter (pg/mL), respectively], with ROC analysis supporting its clinical relevance (P<0.01). Also, significant variation was noted in levels of IL-37 in correlation with HBV serological markers, particularly in patients with negative HBsAg and anti-HBcAb (119.8 vs 63.16 pg/mL, respectively). Conclusions: IL-37, in combination with liver enzymes, may serve as a valuable biomarker panel for monitoring HBV infection.