Cissus cornifolia is an annual herb used in the treatment of mental derangement in the African Traditional Medicine. As part of a continuous research on this medicinal plant to scientifically validate its use in mental derangement, the fractions of the leaf extract were investigated for central nervous system (CNS) depressant effects. Successive fractionation of the methanol leaf extract of C. cornifolia was utilized to obtain the chloroform fraction (CLF), ethyl acetate fraction (EAF) and the residual aqueous fractions (RAF). These fractions were investigated for CNS-depressant effects in mice using diazepam-induced sleep, head-dip and motor-coordination tests. CLF, EAF and RAF significantly (p<0.01) prolonged the duration of sleep in mice. EAF significantly (p<0.05) reduced the mean head-dips in mice at 75 and 150 mg/kg. Similarly, a significant decrease in the mean head-dips (p<0.05, p<0.01 and p<0.005) was produced by RAF at 150, 300 and 600 mg/kg respectively. In the beam-walking assay test, all the fractions did not produce motor coordination deficit in mice. The data obtained revealed the fractions of methanol leaf extract of Cissus cornifolia possess remarkable central nervous system depressant effects.