Isolated congenital heart block (iCHB) is defined as atrioventricular block without structural cardiac defects, characterized by irreversible fibrosis of the cardiac conduction system. Maternal autoantibodies may elicit systemic exaggerated immune responses involving type I interferon (IFN) signalling cascade, yet peripheral circulating immunity in CHB pathogenesis remains poorly understood. To investigate this, we performed single-cell RNA sequencing (scRNA-seq), followed by differential expression gene (DEG) analysis, SCENIC analysis, pseudotime analysis and cell communication analysis, to characterize systemic immune alterations in foetuses with CHB treated with dexamethasone and validated key findings by real-time quantitative PCR (qPCR) and flow cytometry. Compared with controls, CHB foetuses exhibited a markedly activated inflammatory response involving both IFN and NF-κB pathways. Although monocytes showed significant changes in cellular proportions, upregulated DEGs and interferon-stimulated genes, prioritized cellular responses and enhanced intercellular interactions. Notably, THBS1+CD14+ monocytes had a pro-inflammatory phenotype with upregulated NLRP3 inflammasome-related genes and maturation toward a pro-inflammatory state, and Thbs1 conditional knockout mice showed reduced IL-1β levels in BMDMs. Additionally, dexamethasone-treated monocytes had downregulated SOD2 (anti-apoptotic) levels compared to controls, confirmed by qPCR, and flow cytometry verified that dexamethasone promoted monocyte apoptosis. In conclusion, the peripheral immune system in CHB is characterized by innate immune activation driven mainly by monocytes, along with systemic inflammation including IFN signalling. THBS1+/CD14+ monocytes represent a distinct proinflammatory phenotype potentially linked to NLRP3-mediated inflammatory responses.