The in vivo antitrypanosomal potentials of Combretum molle were investigated. The invivo activity of the fractions at (15mg/kg and 10mg/kg) were compared with standard diminazene aceturate (Diminal) at (3.5 mg/Kg), both methanolic and aqueous fractions containing saponins and flavonoids respectively were also fractionated and used for intraperitoneal treatment of mice infected with Trypanosoma brucei brucei federe strain. The Lethal Dose (LD50) were (28.98 mg/kg) and (14.14 mg/kg) respectively for both methanolic and aqueous crude extracts. The haematological profile showed a significant difference (t-test= 9.116; p-value= 0.001) between the pre-infection and post infection and treatment values of packed cell volume (PCV) of the infected mice. However, there was no significant difference in the values of neutrophils, lymphocytes as well as the total white blood cell (WBC) counts. The results showed that Combretum molle had mild in vivo activity, hence can serve as a promising candidate for drug development against trypanosomosis.