Facile and controllable methodologies capable of providing single atom catalysts (SACs) with high-density active metal sites and sintering-resistance under harsh conditions are highly desired and grand challenges in heterogeneous catalysis. Herein, the entropy effect was leveraged to stabilize and manipulate the electronic properties of copper SACs. The as-developed ultrasonication-driven approach could integrate highly concentrated Cu SAs within the lattice of fluorite-structured high entropy oxide (HEFO) under ambient conditions (CuO-HEFO). The dual benefits from the high entropy effect of the support and the in-situ lattice engineering led to the generation of abundant Cu1+ species and oxygen defects, together with ultra-high stability and sintering-resistance under extremely harsh conditions. This was confirmed by deploying non-high entropy support (CuO-CeO2) or Cu sites located on the surface of HEFO (CuO@HEFO). The catalytic activity of CuO-HEFO surpassed that of CuO-CeO2 and CuO@HEFO in CO oxidation together with well-maintained long-term stability and resistance to gas impurities.