Pentraxin 3 (PTX3) responds rapidly to inflammatory signals. This study investigated the functional involvement of PTX3 in angiotensin II (Ang II)-mediated cardiac hypertrophy pathogenesis, with particular focus on its potential regulation through inflammatory pathways and oxidative stress mechanisms. In vivo, chronic Ang II infusion over 4 weeks was used to induce hypertrophic cardiomyopathy in mice. In parallel, an in vitro model of cardiomyocyte hypertrophy was established by treating neonatal rat cardiomyocytes (NRCMs) with Ang II for 24 h. Ang II treatment significantly increased PTX3 expression, an effect observed in both mouse heart tissue and NRCMs. The cardiac hypertrophy and fibrosis in mice treated with Ang II were alleviated by PTX3 knockout. Genetic ablation of PTX3 attenuated Ang II-induced upregulation of cardiac hypertrophy markers in mice hearts, including atrial natriuretic peptide, brain natriuretic peptide, and beta-myosin heavy chain. Additionally, PTX3 knockout suppressed the elevation of pro-inflammatory cytokines, including tumour necrosis factor-alpha and interleukin-1beta, following Ang II stimulation. Genetic deficiency of PTX3 significantly ameliorated cardiac oxidative stress potentiated by Ang II infusion. These outcomes showed that targeting of PTX3 could ameliorate hypertrophic cardiomyopathy via attenuation of inflammatory response and oxidative stress. PTX3 may be a target for therapy of hypertrophic cardiomyopathy in the future.