Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. The role of cardiac long non-coding RNAs in cardiac hypertrophy and cardiomyopathy is not well understood. lincRNA-p21 was induced in mouse and human cardiomyopathy tissue. Global and cardiac-specific lincRNA-p21 knockout significantly suppressed pressure overload-induced ventricular wall thickening, stress marker elevation, and deterioration of cardiac function. Genome-wide transcriptome analysis and transcriptional network analysis revealed that lincRNA-p21 acts in trans to stimulate the NFAT/MEF2 pathway. Mechanistically, lincRNA-p21 bound to the scaffold protein KAP1. lincRNA-p21 cardiac-specific knockout suppressed stress-induced nuclear accumulation of KAP1, and KAP1 knockdown attenuated cardiac hypertrophy and NFAT activation. KAP1 positively regulated pathological hypertrophy by physically interacting with NFATC4 to promote the overactive status of NFAT/MEF2 signaling. Importantly, GapmeR ASO depletion of lincRNA-p21 similarly inhibited cardiac hypertrophy and adverse remodeling, highlighting the therapeutic potential of inhibiting lincRNA-p21. Overall design: To elucidate the mechanisms underlying the salutary effect of lincRNA-p21 inhibition, we used cultured neonatal mouse cardiomyocytes (CMs) treated with the hypertrophic agonist phenylephrine (PE) for 24 hours to simulate the short-term hypertrophic response in CMs. To avoid the potential effect on cis regulatory elements and nascent RNA products resulting from genomic DNA manipulation, we utilized GapmeR antisense oligonucleotide (ASO) to knockdown the linRNA-p21 level (gr-Lp21) through RNase H-dependent degradation mechanisms.