Malaria is an inflammatory cytokine driven disease that sometimes results in death due to lyses of red blood cells. The disease presents a major health challenge to the world especially in tropical and subtropical areas. The aim of this research was to evaluate the modulation of cytokine expression and in vivo antimalarial activity of the residual aqueous fraction (RAF) of methanol leaf extract of Ficus asperifolia (FaMLE). The extract was dissolved in distilled water and serially partitioned with solvents of different polarity to obtain the residual aqueous fraction. Standard protocol was used to determine the preliminary phytochemical and OECD method was used to evaluate the acute toxicity of the extracts. The antimalarial activity was evaluated in mice infected with chloroquine sensitive plasmodium berghei. Oral LD50 of the extracts were estimated to be >5000 mg/kg. The RAF at all doses produced a significant (p<0.05) suppressive, prophylactic, and curative antimalarial activity. The extract also significantly prolonged the survival time of the treated mice compared to the distilled water group. There was a statistically significant (p<0.05) reduction in the mean values of pro inflammatory cytokines assayed (IL-1β, TNFα and IFN-γ) in the RAF treated groups compared with the distilled water treated group. In conclusion RAF possesses antimalarial activity which might have been achieved through modulation of cytokine expression among other possible mechanisms.