Atherosclerosis (AS), the leading cause of cardiovascular diseases, is a chronic inflammatory disorder involving lipid metabolism, immune dysregulation, and cell death. Pyroptosis, a form of inflammatory programmed cell death, is implicated in AS progression, yet its molecular mechanisms and therapeutic potential remain incompletely understood. A multi-omics framework integrating transcriptomics, single-cell RNA sequencing, and machine learning to identify and prioritize pyroptosis-related genes (PRGs) in AS. Functional enrichment, immune infiltration profiling, and protein-protein interaction network analyses were conducted. Experimental validation was conducted using in vitro and in vivo models. Thirty-six PRGs were identified, with TREM2, TNF, MMP9, IL1B, and CASP1 emerging as key regulators of pyroptosis and inflammation. These PRGs demonstrated robust diagnostic potential in internal and external datasets. Immune infiltration analysis stratified AS patients into subtypes, with Cluster 2 characterized by elevated macrophage pyroptosis and a pro-inflammatory immune microenvironment. Single-cell analysis confirmed TREM2 upregulation in macrophages and monocytes, linking it to immune activation and plaque instability. Experimental validation revealed TREM2's dual role in promoting macrophage lipid accumulation and pyroptosis. This study establishes PRGs, particularly TREM2, as critical modulators of AS progression. These findings enhance our understanding of pyroptosis in AS and provide a framework for developing PRG-based diagnostic and therapeutic strategies.