Elansolids A1/A2, B1–B3, and A3 are new metabolites from Chitinophaga sancti with a bicyclo[4.3.0]nonane core possibly arising from intramolecular Diels–Alder cycloaddition (IMDA). Herein we describe the identification of the elansolid biosynthetic gene cluster and details on the unique aspects of elansolid biosynthesis, focusing particularly on the proposed IMDA cycloaddition and macrolactonization, approached through two directions: a) identification and analysis of the biosynthetic polyketide synthase (PKS) machinery including feeding studies, and b) synthesis of model precursors and synthetic studies on the IMDA cycloaddition. Feeding studies revealed elansolids are polyketide-derived with a chorismate-derived p-hydroxybenzoic acid starter unit. The biosynthetic gene locus is a trans-AT PKS including six AT-less PKS subunits (J,K,O,P,Q,R) and two trans-AT functions (elaB, elaC). Based on domain architecture and phylogenetic analysis, a biosynthetic model was proposed. Synthetic model studies with all-E triene 11 and regioisomer 12 showed that oxidation of allyl alcohols to enones led to spontaneous IMDA cycloaddition, with product configurations at C16, C19, C23, and C24 identical to elansolids. We also analyzed quinone methide moieties as key intermediates: the quinone methide intermediate undergoes IMDA to form the bicyclo[4.3.0]nonane core, followed by Michael-type carboxylate attack to yield elansolid A1, or nucleophilic attack by water/methanol/ammonia to form elansolids B1–B3. In conclusion, we detailed the PKS-based biosynthesis of elansolids, shedding light on the unprecedented quinone methide-initiated IMDA cycloaddition/macrolactonization.