In the era of drug repurposing, speedy discovery of new therapeutic options for the drug-resistant malaria is the best available tactic to reduce the financial load and time in the drug discovery process. Six anticancer drugs, three immunomodulators and four antibiotics were selected for the repositioning against experimental malaria owing to their mode of action and published literature. The efficacy of existing therapeutics was evaluated against chloroquine-resistant in vitro and in vivo strains of Plasmodium falciparum and P. yoelii, respectively. All the pre-existing FDA-approved drugs along with leptin were primarily screened against chloroquine-resistant (PfK1) and drug-sensitive (Pf3D7) strains of P. falciparum using SYBR green-based antiplasmodial assay. Cytotoxic profiling of these therapeutics was achieved on Vero and HepG2 cell lines, and human erythrocytes. Percent blood parasitemia and host survival was determined in chloroquine-resistant P. yoelii N67-infected Swiss mice using appropriate doses of these drugs/immunomodulators. Antimalarial screening together with cytotoxicity data revealed that anticancer drugs, idelalisib and 5-fluorouracil acquired superiority over their counterparts, regorafenib, and tamoxifen, respectively. ROS-inducer anticancer drugs, epirubicin and bleomycin were found toxic for the host. Immunomodulators (imiquimod, lenalidomide and leptin) were safest but less active in in vitro system, however, in P. yoelii-infected mice, they exhibited modest parasite suppression at their respective doses. Among antibiotics, moxifloxacin exhibited better antimalarial prospective than levofloxacin, roxithromycin and erythromycin. 5-Fluorouracil, imiquimod and moxifloxacin displayed 97.64, 81.18 and 91.77 % parasite inhibition in treated animals and attained superiority in their respective groups thus could be exploited further in combination with suitable antimalarials.