Background: Crossopteryx febrifuga is monospecific plant from Rubiaceae family that is widely distributed in savannah and tropical regions of Africa particularly in Nigeria. Ethnomedicinally, the leaves of this plant has been used for treatment of skin infections in Nupeland, Nigeria. However, there were no reports on the methanol extract of Crossopteryx febrifuga leaves against Multi-resistant Staphylococcus aureus (MRSA) and its Gas Chromatography-Mass Spectrometry (GC-MS) analysis. The present study was aimed to determine the bioactive constituents in the methanol extract of Crossopteryx febrifuga leaves against Multi-resistant Staphylococcus aureus skin infections by GC-MS analysis. The methanol extract of Crossopteryx febrifuga leaves was characterized for its phytochemical composition by phytochemical screening and GC-MS analysis using standard methods. The phytochemical screening of the crude extract and the ethyl acetate fraction revealed the presence of flavonoids, tannins, saponins, steroids and anthraquinones while the GC-MS chromatogram revealed some peaks that represent fourteen compounds identified by their retention time and peak height. These compounds are: 6-methylenebicyclo [3, 2, 0] hept-3-en-2-one (C8H8O), phenol (C6H5OH) and phenol, 2, 6-dimethoxy- (C8H10O3) with 31.56 %, 29.507 % and 8.417 % percentage areas respectively. Others are 2-methoxy-4-vinylphenol (C7H10O2) at 7.533 %; phenol, 2-methoxy (C7H8O2) at 6.308 %; benzylmethanol (C7H8O)at 4.559 %; 2H-1-benzopyran-3, 4-diol, 2-(3,4-dimethoxyphenyl)-3, 4- dihydro-6-methyl-, (2α, 3α, 4α)- (C18H16O5)at 2.995 %; 10, 11-dihydro -10- dydroxy-2, 3-dimethoxy-dibenz (b, f) oxepin (C16H16O4) at 2.169 %; Cyclopenta [1,3] cyclopropa [1,2] cyclohepten-3 (3aH)-one, 1, 2, 3b, 6, 7, 8–hexahydro-6, 6-dimethyl (C13H18O)at 1.453 %; 2-furancarboxaldehyde,5-methyl (C6H6O2) at 1.353 %; levoglucosenone (C6H6O3) at 1.248 %; ethanone, 1-(1-cyclohexane-1-yl)- (C8H12O) at 0.976 %; 6-oxa-bicyclo[3,1,0] hexane-3-one (C5H6O2) at 0.962 % and benzofuran, 3-methyl (C9H7O) at 0.956 %. The presence of these chemical principles is an indication that the methanol extract of C. febrifuga leaves may yield compounds of pharmaceutical importance against MRSA skin infections if purely isolated.