Microporous polyethylene (PE) membrane is a representative lithium-ion battery (LIB) separators but regularly shrinks especially in high-temperature conditions, and is facilely pierced while growing Li dendrites, leading to severe consequences such as short circuits, thermal runaway, and even explosion. Herein, this article reports a quasi-continuous strategy that utilizes in situ enamel mineralization engineering followed by thermal treatment to easily develop a large-area, 3D interlaced hydroxyapatite nanosheets array-reinforced PE nanocomposite separator with robust mechanical properties and excellent resistance to thermal shrinkage. Specifically, the 120 °C-heated nanocomposite possesses excellent breaking stress, an ultrahigh toughness of ≈434.4 MJ m−3, and an enhanced friction coefficient of ≈0.69, which are distinctly higher than those of commercial PE separators, respectively, and far exceeding those of reported ceramic modified-PE separators. The elongation of the resultant nanocomposite can achieve an extraordinary ≈2456.4% without any fracture under a 180 °C-heating temperature. In situ observation and finite element simulation indicate that the impressive mechanical and thermostable integration profits from the co-effect of efficient energy dissipation at organic–inorganic interfaces and mechanically interlocked, mutually-supported hybrid microstructure. The enamel-inspired separator can be potentially applied in safer high-temperature LIBs and this strategy provides a valuable guide to develop other high-performance polymer-based nanocomposites.