<jats:title>Abstract</jats:title><jats:p>Bipolarolides A–G (<jats:bold>1</jats:bold>–<jats:bold>7</jats:bold>), seven novel ophiobolin‐derived sesterterpenes with three new types of skeletons, were characterized from fungus <jats:italic>Bipolaris</jats:italic> sp. TJ403‐B1. Their structures were determined via spectroscopic analyses, X‐ray crystallography, and quantum chemical <jats:sup>13</jats:sup>C NMR and electronic circular dichroism (ECD) calculations. Compounds <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold> were uniquely defined by a multicyclic caged oxapentacyclo[9.3.0.0<jats:sup>1,6</jats:sup>.0<jats:sup>5,9</jats:sup>.1<jats:sup>8,12</jats:sup>]pentadecane‐bridged system. Compounds <jats:bold>3</jats:bold> and <jats:bold>4</jats:bold> featured an unprecedented 5‐5‐5‐5‐fused core skeleton, while <jats:bold>3</jats:bold> also contained an unexpected C‐3–C‐14 oxygen bridge to construct the caged architecture. Compounds <jats:bold>5</jats:bold>–<jats:bold>7</jats:bold> form a new class of highly modified pentacyclic oxaspiro[4.4]nonane‐containing sesterterpene‐alkaloid hybrids. Their biosynthetic pathways and potential HMG‐CoA reductase inhibitory and antimicrobial activities are also discussed.