National Natural Science Foundation of China (81841001) and the Major National Science and Technology Program of China for Innovative Drug (2017ZX09101002-001-001-05). We further acknowledge generous support by FAPESB (Brazil, grant number APP0088/2016) and Fiocruz/Inova (grant number 1642178247). A CNPq scholarship for M.C.B.S. and financial support by the German Academic Exchange Service (DAAD) through a doctoral research fellowship for A.C¸ is gratefully acknowledged.A substantial challenge worldwide is emergent drug resistance in malaria parasites against approved drugs, such as chloroquine (CQ). To address these unsolved CQ resistance issues, only rare examples of artemisinin (ART)-based hybrids have been reported. Moreover, protein targets of such hybrids have not been identified yet, and the reason for the superior efficacy of these hybrids is still not known. Herein, we report the synthesis of novel ART-isoquinoline and ART-quinoline hybrids showing highly improved potencies against CQ-resistant and multidrug-resistant P. falciparum strains (EC50  (Dd2) down to 1.0 nm; EC50  (K1) down to 0.78 nm) compared to CQ (EC50  (Dd2)=165.3 nm; EC50  (K1)=302.8 nm) and strongly suppressing parasitemia in experimental malaria. These new compounds are easily accessible by step-economic C-H activation and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reactions. Through chemical proteomics, putatively hybrid-binding protein targets of the ART-quinolines were successfully identified in addition to known targets of quinoline and artemisinin alone, suggesting that the hybrids act through multiple modes of action to overcome resistance.