Alzheimer's disease (AD) is one of the leading causes of death for people over 65 years. Worse still, no completely effective therapeutic agent is available so far. One important pathological hallmark of AD is accumulated amyloid-β (Aβ) plaques with dysregulated metal homeostasis. Human metallothionin 3 (MT3), a regulator of metal homeostasis, is downregulated at least 30% in AD brain. So far, some in vitro studies demonstrated its multiple functions related to AD. However, it is a great pity that systematic in vivo studies of MT3 on AD model animals are still a blank so far. In this study, we treated APP/PS1 mice with sustained drug release of Zn7MT3 directly to the central nervous system, and investigated the role and molecular mechanism of Zn7MT3 to protect against AD mice systematically. The results demonstrated that Zn7MT3 can significantly ameliorate cognitive deficits, regulate metal homeostasis, abolish Aβ plaque load, and reduce oxidative stress. Additionally, it has been confirmed that MT3 is penetrable to the blood brain barrier of AD mice. All these results support that Zn7MT3 is an effective AD suppressing agent and has potential for applications in Alzheimer's disease therapy.