Four new azaphilones, penicilones A-D (1-4), were isolated from the mangrove rhizosphere soil-derived fungus Penicillium janthinellum HK1-6. Their planar structures and absolute configurations were determined by extensive analysis of NMR spectroscopic data, ECD spectra, the modified Mosher's method, and chemical conversions. Interestingly, 1 and 2 had the opposite configuration at C-7 compared to the closely related chloro analogues 3 and 4. Ester hydrolysis of 2 and 4 afforded their parental azaphilones, named penicilones E (5) and F (6). Compounds 1-6 were evaluated for their antibacterial activities in vitro. Penicilones B-D (2-4) showed potent anti-MRSA (Staphylococcus aureus ATCC 43300, ATCC 33591) activities with MIC values ranging from 3.13 to 6.25 μg/mL.