Objective To investigate the effect of calorie restriction (CR) cardiomyocyte hypertrophy induced by angiotensin Ⅱ (AngⅡ) and the possible mechanisms involved. Methods H9c2 cells were divided into six groups: Control, AngⅡ (1 μmol/ L), CR, CR+AngⅡ, CR+AngⅡ+Ss and CR+AngⅡ+Bet groups. The cell viability of each group was detected using the CCK-8 method after corresponding drug treatments. The surface area of cardiomyocytes was detected by TRITC-phalloidin staining. The concentrations of lactic dehydrogenase (LDH), myeloperoxidase (MPO), Reactive oxygen species(ROS), Superoxide dismutase(SOD), and Malondialdehyde(MDA) in cell culture supernatants were detected with kits. The mRNA expression of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP),myosin heavy chain-β ( β-MHC), NOD-like receptor protein 3 ( NLRP3), apoptosis-associated speck-like protein ( ASC), the protein levels of NLRP3, ASC, GSDMD, caspase1 and Nuclear factor-κB(NF-κB) in cardiomyocytes were detected by Western blot. Results The surface area of H9c2 cardiomyocytes and the mRNA expression levels of hypertrophy markers(ANP, BNP, β-MHC) were significantly increased in Ang Ⅱ-induced H9c2 cardiomyocytes compared with the controls, and these changes were attenuated by CR intervention. CR reversed the AngⅡ-induced increase in LDH and MPO in myocardium mast cells. The mRNA expression levels of NLRP3, ASC, GSDMD, caspase1, IL-18, and IL-1β and the protein levels of NLRP3, ASC, GSDMD, caspase1, and NF-κB were significantly decreased in Ang Ⅱ-induced hypertrophied cardiomyocytes under CR intervention compared with Ang Ⅱ only. An NF-κB inhibitor further reduced the mRNA expression of NLRP3 and GSDMD compared with expression in the CR+Ang Ⅱ group, while an NF-κB agonist blocked the effect of CR on the mRNA expression of coke-death related genes. Conclusions CR reduced the cardiomyocyte hyperplasia induced by Ang Ⅱ in rats, and it may protect cardiomyocytes by inhibiting pyroptosis through the regulation of NF-κB.