Herbal combinations when used together may sometimes produce enhanced, same or diminished effect. As a result, herb combinations used in the management of diabetes mellitus need to be thoroughly investigated to provide the best effect in reducing the major underlying cause (hyperglycemia) of the disease. Aqueous extracts of Gymnema sylvestre (GS) and Combretum micranthum (CM) leaves were subjected to solvent-solvent partitioning along different polarities. The best fractions (methanol) in terms of in vivo fasting blood glucose (FBG) in alloxan-diabetic mice were subjected to column chromatography and preparative-TLC to obtain sub-fractions and sub-sub-fractions respectively. Sub-fractions D and G for GS and CM respectively gave the best reduction in FBG in vivo while sub-sub-fractions D4 and G4 yielded highest percentage reduction in FBG in alloxan-diabetic mice. The probable mode of action of the phenolic compounds identified by UHPLC-QTOF-MS/MS in both plants could be by inhibiting activities of α-amylase and α-glucosidase. At a dose of 10 mg/kg body weight, a 1:1 combination of GS-D4 and CM-G4 sub-sub-fractions, containing mainly phenolic compounds, significantly (P < 0.05) reduced FBG to 58.25±7.54% in 2 hours and 69.11±6.78% in 4 hours in a synergistic manner.