Malaria is one of the most important infectious diseases in Africa especially in Cameroon. The nonaccessibility to current treatments for poor people and the appearance of drug-resistant Plasmodium falciparum parasites stimulate the search for alternative treatments. The aim of this study was to evaluate the antimalarial activity and the safety of hydroethanolic extracts from Erigeron floribundus and Azadirachta indica. The crude hydroethanolic extracts of E. floribundus (HEEF) and A. indica (HEAI) were prepared via maceration of the whole plant powder of E. floribundus and the leaves of A. indica in 70% ethanol. The antimalarial activity was determined according to Peter's 4-day suppressive test using the murine model Plasmodium berghei/Balb C mice, while the acute and subacute toxicity tests were assessed according to the OECD 425 and 407 guidelines, respectively. The results indicate a reduction of parasitemia ranging from 49.75 ± 3.64 to 69.28 ± 1.36% for HEAI and from 30.46 ± 4.30 to 62.36 ± 2.32% for HEEI. Overall, HEEF and HEAI at doses of 60, 120, and 240 mg/kg b.w. and 75, 150, and 300 mg/kg b.w., respectively, showed a significant (p≤0.001) parasitemia reduction on P. berghei infecting BALB/c mice. HEEF and HEAI caused a significant (p<0.001) attenuation of body temperature drop in mice compared to negative control, except for the 150 mg/kg b.w. dose in the female group. Moreover, there was no mice mortality observed with these extracts even at 5000 mg/kg, while the aspartate amino transferase (ASAT) level of mice treated with 300 mg/kg b.w. of HEAI extract increased when compared with the control. The results of this study support the traditional use of these plants species extracts against malaria infection in rural zones of Northern Cameroon, therefore confirming their potential as sources for the development of efficient phytomedicines for malaria-poverty disease alleviation.