Abstract: With the rapid development of China’s non-ferrous metal smelting industry, the accumulation of solid waste at smelting sites and the contamination of soil and groundwater by heavy metals have become increasingly prominent, emerging as critical constraints on regional ecological restoration and sustainable development. Conventional remediation technologies are often limited by high costs and a significant risk of secondary pollution. In contrast, microbial-mediated in situ remediation has gained increasing recognition due to its cost-effectiveness and environmental sustainability, positioning it as a promising approach for addressing heavy metal pollution. High-throughput sequencing technology, as an advanced bioinformatics tool, offers robust support for elucidating the response mechanisms of soil microorganisms under heavy metal stress. By integrating multi-omics approaches, including 16S rRNA amplicon sequencing, metagenomic sequencing, metatranscriptomic sequencing, and metaproteomic sequencing, this technology enables a systematic investigation of the structure-function relationships within microbial communities at contaminated smelting sites and clarifies their specific roles in heavy metal transformation processes. Findings indicate that heavy metal stress significantly alters the composition of soil microbial communities and influences the abundance and diversity of key functional taxa. High-throughput sequencing has further identified microbial activity in critical metabolic pathways such as heavy metal resistance, reduction, sulfide precipitation, and organic acid chelation, thereby elucidating the underlying microbial mechanisms of heavy metal immobilization and detoxification. In a case study involving the remediation of a lead-zinc smelting site in Guangxi, high-throughput sequencing facilitated the strategic combination of functional bacteria and genus-specific strains to construct an efficient synthetic microbial consortium. This approach led to a substantial reduction in heavy metal concentrations in both soil and leachate, resulting in marked improvement in the environmental quality of the site. This successful application provides a scientific foundation and practical model for the remediation of similar contaminated sites, highlighting the transformative potential of high-throughput sequencing in advancing eco-friendly and targeted environmental restoration technologies.