A unique polyketide cladosporactone A along with eight known compounds were isolated from the deep‐sea‐derived Cladosporium cladosporioides. The structure of cladosporactone A was established by spectroscopic analyses, and the absolute configuration was clarified by the theoretical ECD calculation. Cladosporactone A is the first member of polyketide with the 7‐methylisochromen‐3‐one skeleton.