Parasitic nematodes, especially Haemonchus contortus (Rudolphi), are among the most common and economically important causes of disease in sheep and goats owned by pastoralists and small holder farmers in Africa. The control of these infections relies mainly on the use of anthelmintic drugs. However, herbal preparations are widely used by pastoralists and small holder farmers for the treatment of their livestock against helminth parasites. The anthelmintic effect of acetone leaf extract and fractions of Combretum molle was investigated to determine the relative efficacy of the components against gastrointestinal sheep nematodes. The fractions were obtained by solvent:solvent extraction from the acetone extract. These were evaluated for nematocidal activity by means of an egg hatch (EHA) and larval a development and viability assay (LDVA) in vitro. The effect of the test extracts on the hatchability of eggs and development of first to third stage larvae and the survival rate of the third stage larvae. H. contortus, were used to determine the relative bioactivities. Best-fit LC50 values were computed using global model of nonlinear regression curve-fitting. The extracts inhibited egg hatching and development of the larvae of H. contortus in a concentration-dependent manner. Best-fit LC50 values for the egg hatch test were 0.866, 0.333, 0.833, 0.747, and 0.065 mg/mL for acetone extract, n-butanol, hexane, chloroform, and 35% water in methanol fractions, respectively. The best-fit LC50 values for the LDVA were 0.604, 0.362, 1.077, 0.131 and 0.318 mg/mL for the acetone extract, butanol, hexane, chloroform, and 35% water in methanol fractions, respectively. In the EHA the 35% water in methanol fraction was significantly more active than all the other fractions (p < 0.05); however the activity was not significantly different with the LDVA. C. molle leaf could find application in anthelmintic therapy in veterinary practice.