Background and Objective: CHB is a complex heterogeneous disease with a high incidence and mortality rate. Especially, the mutant strains with A1762T/G1764A and G1896A mutations gradually gained survival advantages during the population evolution process. However, our current understanding of the potential pathogenic mechanism of the mutant strains is limited. Our goal is to use multi-omics analysis to elucidate the potential molecular mechanisms, develop biomarkers for assessing the severity of the disease, and explore potential therapeutic targets. Methods: Based on the sequencing results of serum HBV DNA in the samples, we finally included 108 patients with chronic hepatitis B. According to the sequencing results, they were divided into groups A (wild strain, WT = 27), B (G1896A = 27), C (A1762T/G1764A = 27), and D (A1762T/G1764A + G1896A = 27). We conducted non-target metabolomics and proteomics analyses to investigate the changes in the metabolism of infected liver cells caused by different site mutations. We selected the A1762T/G1764A group and the A1762T/G1764A + G1896A group for comparative analysis with the WT group, aiming to gain a deeper understanding of the pathogenic mechanism of the dominant mutant strains. Results: Compared with WT, the A1762T/G1764A group and the A1762T/G1764A + G1896A group identified 242 and 64 as well as 226 and 79 differentially expressed metabolites and proteins, respectively. Through ipath pathway analysis and KEGG pathway mapping analysis, we found that A1762T/G1764A and A1762T/G1764A + G1896A might aggravate liver injury by affecting base repair and increase lipid accumulation in liver cells by down-regulating cholesterol metabolism. In the A1762T/G1764A + G1896A group, four proteins, APOC2, APOA2, CETP, and ANGPTL4, coordinated their functions to inhibit lipid metabolism and aggravate lipid accumulation in liver cells. Conclusion: A1762T/G1764A and G1896A mutations may affect base repair and aggravate liver cell damage, and at the same time, by down-regulating the cholesterol metabolism pathway, aggravate lipid accumulation in liver cells and accelerate disease progression.