Heart failure (HF) affects over 64 million people worldwide causally linked to fibrotic scarring. None of the available cardiac drugs target fibrosis directly, underlining unmet clinical need for novel therapies. This study aimed to explore the therapeutic potential of the cysteine protease inhibitor aloxistatin as a repurposed drug candidate to combat fibrotic progression in predictive HF models. Aloxistatin reduced migratory and proliferative capacities of human cardiac fibroblasts (HCFs) derived from various HF backgrounds. Mechanistically, aloxistatin attenuated TGFβ1-induced pro-fibrotic signaling in cardiomyopathy-derived HCFs by inhibiting extracellular matrix organization-related gene expression and secretion of MMP2 und FN1, partially mediated through CAPN2 inhibition. Transcriptomic analysis of rat ex vivo myocardial slices revealed a pronounced suppression of inflammatory pathways. Anti-inflammatory effects of aloxistatin were further confirmed by reduced NFκB activity in reporter cells and inhibited HLA-DR expression in human iPSC-derived macrophages. Application of diverse preclinical cardiac HF models arguably underlined aloxistatin as a potential drug repurposing strategy by simultaneously counteracting myocardial inflammatory signaling and pro-fibrotic mechanisms. This preclinical study suggests aloxistatin therapy for translational use to attenuate cardiac remodeling and progression of heart failure.