Besides targeting amyloid or tau metabolisms, regulation of redox metal ions is a recognized therapeutic target for Alzheimer’s disease (AD). Based on the bioinorganic chemistry of copper, we designed specific chelators of copper(II) (TDMQs) insight to regulate copper homeostasis in the brain and to inhibit the deleterious oxidative stress catalyzed by copper-amyloid complexes. An oral treatment by TDMQ20 was able to fully reverse the cognitive and behavioral impairment in three different murine models, two nontransgenic models mimicking the early stage of AD and a transgenic model representing a more advanced stage of AD. To our knowledge, such a comparative study using the same molecule has never been performed. Regular C57BL/6 mice received a single injection of human Cu-Aβ1–42 in the lateral ventricles (icv-CuAβ) or in the hippocampus (hippo-CuAβ). In both cases, mice developed a cognitive impairment similar to that of transgenic 5XFAD mice. Oral administration of TDMQ20 to icv-CuAβ or hippo-CuAβ mice within a 16-day period resulted in a significant improvement of the cognitive status. The 3-month treatment of transgenic 5XFAD mice with TDMQ20 also resulted in behavioral improvements. The consistent positive pharmacological results obtained using these different AD models correlate well with previously obtained physicochemical data of TDMQ20. The short-term novel object recognition (NOR) test was found particularly relevant to evaluate the rescue of declarative memory impairment. TDMQ20 was also able to reduce the oxidative stress in the mouse cortex. Due to its reliability and facile use, the hippo-CuAβ model can be considered as a robust nontransgenic model to evaluate the activity of potential drugs on the early stages of memory deficits.