Thermally conductive polymer nanocomposites integrated with lightweight, excellent flexural strength, and high fracture toughness (K ) would be of great use in many fields. However, achieving all of these properties simultaneously remains a great challenge. Inspired by natural nacre, here we demonstrate a lightweight, strong, tough, and thermally conductive boron nitride nanosheet/epoxy layered (BNNEL) nanocomposite. Because of the layered structure and enhancing the interfacial interactions through hydrogen bonding and Si–O–B covalent bonding, the resulting nacre-inspired BNNEL nanocomposites show high fracture toughness of ∼ 4.22 MPa·m, which is 7 folds as high as pure epoxy. Moreover, the BNNEL nanocomposites demonstrate sufficient flexural strength (∼ 168.90 MPa, comparable to epoxy resin), while also being lightweight (∼ 1.23 g/cm). Additionally, the BNNEL nanocomposites display a thermal conductivity (κ) of ∼ 0.47 W/(m·K) at low boron nitride nanosheet loading of 2.08 vol.%, which is 2.7 times higher than that of pure epoxy resin. The developed nacre-inspired strategy of layered structure design and interfacial enhancement provides an avenue for fabricating high mechanical properties and thermally conductive polymer nanocomposites.[Figure not available: see fulltext.