African trypanosomiasis is still one of the infectious diseases threatening the health of human beings and animals, and severely impeding the continental economic development. Currently, the disease control programs are mainly relying on a limited number of parasiticides which are either expensive or with severe side-effect, and insecticides. In this study, we investigated the anti-trypanosome effect of two noble metal nanoclusters (NM-NCs), Ag2S-NC@MPA and AuNC@GSH. Both types of NCs can be efficiently up-taken by Trypanosoma brucei via a clathrin-dependent endocytosis pathway, and displayed dose-dependent anti-parasite effect by inducing apoptosis-associated organelle pathological alterations. The data not only revealed the clathrin-dependent endocytosis pathway in African trypanosome, but also proposed a new avenue for NM-NC-based drug development for trypanosomiasis.