The 5th subunit of COP9 signalosome (CSN5, also known as Jab1 or COPS5) is implicated in regulating p53 activity and is overexpressed in various tumors. However, the precise roles of CSN5 in p53 network and tumorigenesis are not well characterized. Here we show that CSN5 is a critical regulator of both p53 and MDM2. We show that curcumin, an important inhibitor of CSN-associated kinases, can downregulate not only CSN5 but also MDM2, which results in p53 stabilization. Importantly, CSN5 interacts with p53. CSN5 expression leads to p53 degradation, facilitating MDM2-mediated p53 ubiquitination, and promoting p53 nuclear export. Additionally, CSN5 expression results in stabilization of MDM2 through reducing MDM2 self-ubiquitination and decelerating turnover rate of MDM2. Significantly, we further show that CSN5 antagonizes the transcriptional activity of p53. These results demonstrate that CSN5 is a pivotal regulator for both p53 and MDM2. Our studies may pave the way for targeting CSN5 for anti-cancer drug development.