<jats:title>Abstract</jats:title><jats:p>Two new polyketide derivatives, huaspenones C and D (<jats:bold>1</jats:bold> and <jats:bold>2</jats:bold>, resp.), were isolated from the cultures of an endophytic fungus <jats:italic>Peyronellaea</jats:italic> sp. HS‐12, derived from the stems of <jats:italic>Huperzia serrata.</jats:italic> They share N‐bearing furan‐3(2<jats:italic>H</jats:italic>)‐one backbone, and <jats:bold>2</jats:bold> has an unprecedented furo[3,2‐<jats:italic>c</jats:italic>]pyridine skeleton. Their structures including the absolute configuration were elucidated by extensive spectroscopic analysis combined with quantum‐chemical calculations. (2<jats:italic>E</jats:italic>,4<jats:italic>E</jats:italic>)‐6‐hydroxy‐2‐methylocta‐2,4‐dienoic acid (<jats:bold>3</jats:bold>), a key intermediate of the biosynthesis of <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold>, was also obtained from the endophyte.