An investigation of the jellyfish-derived fungus Penicillium chrysogenum J08NF-4 led to the isolation of two new meroterpene derivatives, chrysogenester (1) and 5-farnesyl-2-methyl-1-O-methylhydroquinone (2), and four known farnesyl meroterpenes. Docking analysis of 1 showed that it binds to PPAR-γ in the same manner as the natural PPAR-γ agonist amorfrutin B (7). Compound 1 activated PPAR-γ in murine Ac2F liver cells and increased nuclear PPAR-γ protein levels in murine RAW 264.7 macrophages. Because one of the main biological functions of PPAR-γ agonists is to suppress inflammatory response, an in vitro study was performed to explore the anti-inflammatory potency of 1 and the mechanism involved. In RAW 264.7 macrophages, 1 inhibited phosphorylation of the NF-κB p65 subunit and suppressed the expression of the pro-inflammatory mediators iNOS, NO, COX-2, TNF-α, IL-1β, and IL-6. We propose 1 suppresses inflammatory responses by activating PPAR-γ and subsequently downregulating the NF-κB signaling pathway, thus reducing the expressions of pro-inflammatory mediators.