The association of a metallic fuel (usually aluminum) with an oxidizer (metal oxide or organic compound) creates an exothermic material that can be ignited with an external stimulus such as local heating or spark discharge. These materials with high energetic performances, called nanothermites, have been used to release temperature or pressure waves for civil or military applications (initiators, impact igniters, etc.). However, the energetic performances of these nanothermites are highly dependent on the nanoscale intimacy of the two components. The use of nanoparticles results in an increase of the energy release, but control of their assembly remains particularly challenging. In this work, we demonstrate that the use of DNA to self-organize Al or CuO nanoparticles greatly enhances the energy release of nanothermites by up to 240% compared to classically sonicated nanothermites in hexane, with the heat of reaction prior to Al melting reaching a value of 2.57 kJ·g–1. In particular, we report that the energetic performances can be tuned by controlling the ionic strength during the self-assembly process. These results are supported by ultrafine characterization of the nanocomposite microstructure based on high-resolution transmission electronic microscopy and energy-dispersive X-ray spectroscopy. Besides, we report the surprisingly good energetic performances of randomly mixed nanoparticles dispersed in water, nonetheless 40% lower than DNA-self-assembled nanocomposites. Altogether, our study not only proposes an easy and immediate process for nanocomposites synthesis but also opens the door for opportunities toward large-scale crystalline Al–CuO superlattices with high energetic performances.