Background <p>Atrial fibrillation (AF) is the most common cardiac arrhythmia, with hypertension as its primary risk factor. While immune dysfunction is known to play a crucial role in hypertension, its specific impact on AF in the hypertensive setting remains underexplored. This study aims to elucidate the immune landscape of AF in the context of hypertension and explore the potential mechanisms.</p> Methods <p>Single-cell RNA transcriptomic analysis was employed to profile peripheral blood mononuclear cells (PBMCs) in hypertensive patients with AF, using hypertensive patients without AF as controls. Flow cytometry, serum cytokine analysis, and cohort studies were used for validation.</p> Results <p>Monocytes were identified as the most significantly affected cell type in hypertensive patients with AF, showing heightened disruption of cholesterol homeostasis and immune-inflammatory responses. Interestingly, a unique cluster of monocyte–platelet aggregates (MPAs) was identified to exhibit the most active intercellular interactions. Flow cytometry confirmed elevated proportions of CD14⁺ monocytes and MPAs in hypertensive patients with AF. Serum analysis of a larger cohort revealed significantly higher levels of C-C motif chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). Integration of single-cell data from blood and cardiac tissue revealed transcriptional patterns consistent with increased monocyte recruitment and differentiation in hypertensive patients with AF. Cohort studies further supported that the increased number of circulating monocytes was associated with a higher incidence of AF in hypertensive patients.</p> Conclusions <p>Our study demonstrated that monocyte activation-mediated inflammatory response might play an important role in the pathogenesis of AF in hypertension. These findings offer new insights into potential therapeutic targets for managing AF in hypertensive patients.</p>