Malignant melanoma is one of fatal diseases with increasing incidence rate all around world. Standard therapy for melanoma is cancer radical surgery with chemotherapy and radiotherapy. However, the effect is far from satisfaction and patients under these treatments still succumb to melanoma, which appeals to lack a safe and effective therapy. Artemisinin and its derivatives are commonly regarded as safe and effective clinical anti-malarial drugs used in clinic for decades. Recently, studies showed artemisinin presented a wide range of bioactivities including anti-cancer effect. However, there is no information available regarding the effect of artemisinin on the melanoma recurrence and metastasis after tumor excision. In present study, we creatively established the post-surgery tumor model with two different melanoma cell lines on balb/c nude mice. Furthermore, we investigated the effect of artemisinin on the melanoma recurrence and metastasis after tumor excision, as well as its underlying mechanism. Our results showed application of artemisinin after tumor excision blocked the melanoma recurrence and metastasis, and extended life appetency of host animal. RNA sequencing results identified several proteins, including c-KIT as critical biomarker in melanoma recurrence and metastasis regulated by artemisinin. Western blot confirmed the downregulation of c-KIT and its downstream signaling targets PI3K/AKT and some EMT (Epithelial-Mesenchymal Transitions) biomarkers. These indicated involvement of c-KIT/PI3K/AKT pathway in anti-melanoma effect of artemisinin. With the role of c-KIT, knock out of c-KIT by Crisper-cas9 blocked the phosphorylation of AKT, and inhibited colony formation, migration, and invasion of B16 melanoma cell. These data suggested artemisinin suppressed melanoma recurrence and metastasis after radical surgery by inhibiting c-KIT/PI3K/AKT signaling pathway.