CSN5 is a critical subunit of the COP9 signalosome (CSN) and has been involved in various cellular processes, but little is known about the role of CSN5 in cardiac disease. In the present study, we found that the expression of CSN5 was increased in Angiotensin II (Ang II)-induced cardiac hypertrophic mice hearts and Ang II-treated cardiomyocytes. We also observed that overexpression of CSN5 significantly inhibited Ang II-induced cardiac hypertrophy, whereas CSN5 silence exhibited the opposite phenotypes. Further investigation demonstrated that CSN5 maintained the activity of AMP-activated protein kinase (AMPK) in cardiomyocyte by enhancement of LKB1. Mechanistically, we found that CSN5 directly interacted and deubiquitinated LKB1 for its stabilization in cardiomyocytes. Finally, our results demonstrated that the anti-hypertrophic effect of CSN5 was partially dependent on stabilization of LKB1. Collectively, these findings suggested that strategies based on activation of CSN5/LKB1 axis might be promising in the treatment of hypertrophic cardiomyopathy.