The neuropharmacological activities of the methanolic and aqueous extract of Wedelia calendulacea stem were screened in rats and mice. The extracts effect on pentobarbital-induced sleeping time, pentylenetetrazole- and styrychnine-induced seizure, spontaneous motor activity, exploratory behaviour, and rota-rod performance (motor coordination) were evaluated. The methanolic extract (20 and 50 mg/kg, i.p.) and aqueous extract (200 and 500 mg/kg, i.p.) produced a significant (p<0.001) prolongation of pentobarbital-induced sleeping time, and reduced the SMA and exploratory behaviour. The extract prolonged onset of the phases of seizure activity but did not protect mice against lethality induced by pentylenetetrazole and strychnine. It also failed to affect the motor coordination test. These results suggest that the extract contained an agent with neuropharmacological activity that may be sedative in nature. In addition, from the crude methanolic extract of Wedelia calendulacea stem a HPLC fingerprint profile and liquid chromatography/sequential mass spectrometry (LC/MS) were performed.