<jats:title>Abstract</jats:title><jats:p>Two bioactive merocytochalasans, epicochalasines A (<jats:bold>1</jats:bold>) and B (<jats:bold>2</jats:bold>), a new class of cytochalasans bearing unexpected scaffolds consisting of fused aspochalasin and epicoccine dimer moieties, were isolated from the liquid culture broth of <jats:italic>Aspergillus flavipes</jats:italic>. Both <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold> possess a hendecacyclic 5/6/11/5/6/5/6/5/6/6/5 ring system containing an adamantyl cage and as many as 19 stereogenic centers; however, the fusion patterns of <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold> differ greatly, thus resulting in different carbon skeletons. The absolute configurations of <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold> were determined by X‐ray diffraction and calculated ECD, respectively. The biogenetic pathways of <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold> are proposed to involve Diels–Alder and nucleophilic addition reactions. Both <jats:bold>1</jats:bold> and <jats:bold>2</jats:bold> induced significant G2/M‐phase cell‐cycle arrest. Furthermore, we found that merocytochalasans induce apoptosis in leukemia cells through the activation of caspase‐3 and the degradation of PARP.