(1) Background: Chronic hepatitis B (CHB) is a widely prevalent chronic liver disease, with a particularly high incidence in China. Recent studies indicate that external influences like a high-fat, high-sugar diet and high temperature and humidity may alter the hepatic immune microenvironment in CHB and hasten liver injury progression in patients. Nonetheless, the cumulative effect of these combined factors on liver damage and the immune remodeling process, along with its regulatory mechanisms, remains uncertain. (2) Objective: This research seeks to clarify the impact of simultaneous exposure to a high-fat, high-sugar diet and a high-temperature, high-humidity environment on CHB liver injury and its primary immunometabolic pathways. (3) Methods: This research employed recombinant adenovirus AdrcccDNA to establish a CHB mouse model (M group), and subsequently developed a combined exposure model through intervention with a high-fat, high-sugar diet and a high-temperature, high-humidity environment (NWS group). Subsequently, multi-omics analysis, WGCNA, immune infiltration analysis, and in vivo and in vitro experiments were employed to evaluate the effects of a high-fat and high-sugar diet combined with high-temperature and high-humidity exposure on the progression of CHB. (4) Results: HE staining, virology, and other results showed that combined exposure worsened liver injury and increased viral replication in CHB mice. WGCNA and immune infiltration analysis revealed CD4⁺ T cells as the key differential immune cells and identified 36 associated core mRNAs. Combined analysis revealed that miR-340-5p was significantly negatively correlated with Psat1 expression and highly associated with the proliferation and function of memory CD4⁺ T cells. In vivo validation indicated that in the NWS group, Psat1 levels were reduced, miR-340-5p levels were elevated, and the percentage of memory CD4⁺ T cells was diminished. After in vitro transfection with miR-340-5p mimics, Psat1 levels were downregulated in AML12 and primary CD4⁺ T cells, indicating that miR-340-5p negatively influences Psat1. (5) Conclusions: This study demonstrates that combined exposure to a high-fat, high-sugar diet and a high-temperature, high-humidity environment may worsen CHB liver injury through miR-340-5p/Psat1-mediated immunometabolic regulation.