The global spread of multi-drug resistant P. falciparum , P. vivax , and P. malariae strains and absence of long-term effective vaccine makes chemotherapy the mainstay of malaria control strategies in endemic settings. The Mossman’s assay and the Organization for Economic Co-operation and Development (OECD), 2001 guideline 423, were used to determine the cytotoxicity and acute oral toxicity of a novel hybrid drug, artesunate-3-Chloro-4(4-chlorophenoxy) aniline (ATSA), in vitro and in vivo, respectively. A modified Desjardins method was used to screen for antiplasmodial activity using P. falciparum (3D 7 and W 2 ) strains in vitro. The Peter’s 4-day suppressive tests (4DTs) was used to evaluate the in vivo antimalaria activity using P. berghei ANKA strain, lumefantrine resistant (LuR), and piperaquine resistant (PQR) P. berghei lines. In silico prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles was assayed using PreADMET online prediction tool. The reference drug in all experiments was artesunate (ATS). Statistical significance between ATSA’s activities in treated and control mice was evaluated by one-way analysis of variance (ANOVA). Results show that inhibitory concentrations-50 (IC 50 ) of ATSA is 11.47 ± 1.3 (3D 7 ) and 1.45 ± 0.26 (W 2 ) against 4.66 ± 0.93 (3D 7 ) and 0.60 ± 0.15 (W 2 ) ng/ml of ATS with a selective index of 2180.91(3D 7 ) and a therapeutic index (TI) of > 71). No mortalities were observed in acute oral toxicity assays and mean weight differences for test and controls were statistically insignificant ( P > 0.05). The in vivo activity of ATSA was above 40% with effective dosage-50 (ED 50 ) of 4.211, 2.601, and 3.875 mg/kg body weight against P. berghei ANKA , LuR, and PQR lines, respectively. The difference between treated and control mice was statistically significant ( P < 0.05). ATSA has high intestinal absorption (HIA) > 95% and has medium human ether-a-go-go related gene (hERG) K + channel inhibition risks. Preclinical and clinical studies on ATSA are recommended to evaluate its value in developing novel drugs for future management of multi-drug resistant malaria parasites.