Cordytropolone (1) and (−)-leptosphaerone A (2) were isolated from the culture broth of the fungus Polycephalomyces nip-ponicus. The structures of these two compounds were elucidated by spectroscopic methods and from a comparison of the spectroscopic data with those reported previously. The structure of 1 was confirmed by X-ray crystallography for the first time while the leptosphaerone class (compound 2) was first isolated as its (+)-antipode from the fungus Polycephalomyces(Cordyceps). The fermentation process was monitored weekly by High performance liquid chromatography analysis for 10 weeks. The predominant compound (1) was produced at ~0.65 mg/mg of dry extract at week 9. Compound 1 exhibited modest antipathogenic fungal activity against Collectrichum musae, Colletotrichum capsici, Colletotrichum gloeosporioides, Fusariumspp. TFPK301, F. spp. FOC1708, and Pestalotia spp. with percentage of mycelial growth inhibition values of 3.74 ± 0.70%, 12.86 ± 1.43%, 0.91 ± 0.56%, 5.46 ± 0.56%, 7.93 ± 0.61%, and 18.75 ± 5.24%, respectively, at 25 μg/mL.