In recent years, aptamer-drug conjugates have been extensively utilized in targeted cancer therapy. To achieve satisfactory treatment efficacy, highly toxic drugs rather than hypotoxic drugs are frequently incorporated into the conjugates, leading to concerns about side effects. The development of efficient aptamer-based targeted cancer therapy using drugs with safe or low-toxicity properties is attractive but has not been widely explored. Inspired by the artemisinin bioactivation pathway, we developed a receptor tyrosine kinase 7 (PTK7)-targeting Sgc8c-artesunate conjugate (SAC) with significantly enhanced cytotoxicity that could inhibit the growth of PTK7 overexpressing cancer cells. SAC respectively inhibited the proliferation of CEM and HCT116 cells 93 and 84 times more than artesunate only. Mechanistic studies revealed that aptamers with PTK7-specific recognition, high-affinity binding, and receptor-mediated internalization promoted the accumulation of artesunate inside the target cells. Artesunate bioactivation related with Fe²⁺ led to the generation of alkyl radicals and reactive oxygen species (ROS), and inhibited the growth of target cells via apoptosis. Moreover, in vivo Cy5-fluorescent imaging of tumor-bearing mice indicated SAC could target and retain at HCT116 tumor site for a much longer time than control groups, further highlighting the potential of exploring artesunate not only for treating malaria but also play as a candidate for cancer therapy.