Two new phenone derivatives penicophenones A (1) and B (2), a new cyclic tetrapeptide penicopeptide A (3), and five known compounds were isolated from the culture broth of Penicillium commune, an endophytic fungus derived from Vitis vinifera. Compounds 1-3 were elucidated by extensive spectroscopic analyses including 1D and 2D NMR and HRESIMS. The absolute configurations of 1 and 3 were determined by comparing its ECD with related molecules and modified Marfey's analysis, respectively. Penicophenone A (1) possesses a rare benzannulated 6,6-spiroketal moiety, which is a new member of the unusual structural class with peniphenone A as the representative. Compound 3 exhibited significant inhibition activities against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in vitro and showed strong binding affinity to 11β-HSD1. Moreover, compound 3 treatments decreased the lipid droplet accumulation associate with the inhibition of 11β-HSD1 expression in differentiate-induced 3T3-L1 preadipocytes. Furthermore, the molecular docking demonstrated that compound 3 coordinated in the active site of 11β-HSD1 is essential for the ability of diminishing the enzyme activity.