Background Hepatitis B virus (HBV), a vaccine-avoidable infection, is a health concern worldwide, leading to liver disorders such as acute self-constraint and chronic hepatitis, liver failure, hepatic cirrhosis, and even hepatocellular carcinoma if untreated. ‘Immunogeneticprofiling,’ genetic variations of the pro- and anti-inflammatory cytokines responsible for regulating the immune responses, cause person-to-person differences and impact the clinical manifestation of the disease. The current experimental–bioinformatics research was conducted to examine whether promoteric IL-18–rs187238 C > G and –rs1946518 T > G and intronic CD14–rs2569190 A > G variations are associated with chronic HBV. Methods A total of 400 individuals (200 in each case and control group) participated in the study and were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The data was also assessed bioinformatics-wise for conservation, genomic transcription and splicing, and protein interactions. Results Findings proposed that unlike the IL-18–rs1946518 T > G and CD14–rs2569190 A > G, the IL-18–rs187238 C > G is a protector against chronic HBV (odds ratio [OR] = 0.62, 95% confidence intervals [CI]: 0.46–0.83, and p = 0.002). The TG/CC/AA, TG/CC/AG, TT/CC/AG, and GG/CC/AA combined genotypes significantly increased chronic HBV risk (p < 0.05), while the IL-18 G/T and G/G haplotypes lessened it (p < 0.05). Moreover, in contrast to the IL-18–rs1946518 T > G, IL-18–rs187238 C > G is likely to create novel binding sites for transcription factors, and the CD14–rs2569190 A > G presumably changed the ribonucleic acid splicing pattern. Conclusions The IL-18–rs187238 C > G might protect against chronic HBV and is likely to generate novel binding sites for transcription factors.