The rapid development of miniaturized, highly integrated, and multifunctional modern electronic devices has generated a growing demand for anisotropic heat dissipation in polymer nanocomposites for thermal management applications. These anisotropic thermally conductive multifunctional polymer nanocomposites use bio-inspired structural design based on natural nacre, which is the gold standard for biomimetics. However, to date, a comprehensive review and critique on the highly-anisotropic thermal conduction of nacre-mimetic nanocomposites is nonexistent. As such, this extensive review of the nacre-inspired highly anisotropic thermal management nanocomposites summarizes the current design strategies, and explains the thermal conduction mechanisms, and factors affecting anisotropic thermal conductivity. Furthermore, the practical applications of the as-prepared nacre-inspired highly anisotropic nanocomposites are highlighted. Finally, the key challenges and potential solution strategies associated with these nacre-inspired highly anisotropic nanocomposites are discussed and outlooks for future research opportunities are also proposed.