Medicinal plants have been of great importance to many traditional communities for many generations. However, there is need to carry out scientific studies in order to confirm the medicinal properties of many plants used traditionally. Cosmos sulphureus (Asteraceae) used by local communities for the treatment of various diseases has showed antioxidant, antibacterial, antifungal and antiplasmodial properties although there are no studies demonstrating its antionchocerca activity. The present study was undertaken to investigate the antionchocerca potential of crude extracts and chromatographic fractions of C. sulphureus using Onchocerca ochengi, a bovine filarial closest in phylogeny to Onchocerca volvulus. Solvent extraction of the parts of C. sulphureus was performed using distilled water, 70% EtOH, MeOH, CH 2 Cl 2 and a mixture of MeOH/CH 2 Cl 2 (v/v). Anthelmintic assay was evaluated on adult worms of O. ochengi and worm viability was assessed biochemically using the dimethylthiazol (MTT) formazan assay. Acute and sub-acute oral toxicities of the promising extract was investigated in mice. The chemical composition of extracts was revealed. EtOH extract of roots showed highest anthelmintic activity with an LC 50 value of 31.01±1.17 µg/mL which was more significant than the one of ivermectin (LC 50 =42.78 µg/mL) used as standard. The other extracts show moderate activities. The most active fraction obtained from EtOH extract of roots had an LC 50 value of 19.10 µg/mL on male worm. For acute toxicity, a single dose of 2000 mg/kg used induced no critical behavioral changes or death. In sub-acute toxicity, daily oral administration of hydro-ethanolic extracts of roots at the dose of 250, 500 and 750 mg/kg revealed disturbances in the normal growth of animals as well as liver and kidney alterations. These results unfold potential sources of novel anti-onchocerca lead compounds and validate the traditional use of the plants in onchocerciasis treatment.