Arrhythmogenic cardiomyopathy (ACM) is a genetic form of heart failure that affects 1 in 5000 people globally and is caused by mutations in cardiac desmosomal proteins including PKP2, DSP , and DSG2. Individuals with ACM suffer from ventricular arrhythmias, sudden cardiac death, and heart failure. There are few effective treatments and heart transplantation remains the best option for many affected individuals. Here we performed single nucleus RNA sequencing (snRNAseq) and spatial transcriptomics on myocardial samples from patients with ACM and control donors. We identified disease-associated spatial niches characterized by co-existence of fibrotic and inflammatory cell types and failing cardiac myocytes. The inflammatory-fibrotic niche co-localized to areas of cardiac myocyte loss and was comprised of FAP (fibroblast activation protein) and POSTN (periostin) expressing fibroblasts and macrophages expressing NLRP3 (NLR family pyrin domain containing 3) and NFĸB activated genes. Using homozygous Desmoglein-2 mutant ( Dsg2 mut/mut ) mice, we identified analogous populations of Postn expressing fibroblasts and inflammatory macrophage populations that co-localized within diseased areas. Detailed single cell RNA sequencing analysis of inflammatory macrophage subsets that were increased in ACM samples revealed high levels of interleukin-1β ( Il1b ) expression. To delineate the possible benefit of targeting IL-1β in ACM, we treated Dsg2 mut/mut mice with an anti-IL-1β neutralizing antibody and observed attenuated fibrosis, reduced levels of inflammatory cytokines and chemokines, preserved cardiac function, and diminished conduction slowing and automaticity, key mechanisms of arrhythmogenesis. These results suggest that currently approved therapeutics that target IL-1β or IL-1 signaling may improve outcomes for patients with ACM.