The difficulty of developing an efficient malaria vaccine along with increasing spread of multidrug resistant strain of Plasmodium falciparum to the available antimalarial drugs poses the need to discover safe and efficacious antimalarial drugs to control malaria. An alternative strategy is to synthesize compounds possessing structures similar to the active natural products or marketed drugs. Several biologically active natural products and drugs contain β-carboline moiety. In the present study, few selected β-carboline derivatives have been synthesized and tested for their in vitro and in vivo antiplasmodial activity against the rodent malaria parasite Plasmodium berghei (NK-65). The designed analogs exhibited considerable in vitro antimalarial activity. Two compounds (1R,3S)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (9a) and (1R,3S)-methyl 1-(pyridin-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (9b) were further selected for in vivo studies. Both the lead compounds (9a and 9b) were observed to be safe for oral administration. The therapeutic effective dose (ED50) for 9a and 9b were determined and in the animal model, 9a (at 50 mg/kg dose) exhibited better activity in terms of parasite clearance and enhancement of host survival. Biochemical investigations also point toward the safety of the compound to the hepatic and renal functions of the rodent host. Further studies are underway to explore its activity alone as well as in combination therapy with artesunate against the human malaria parasite P. falciparum.