Today the alarming situation of diabetes seeks innovative antidiabetic medications, especially those derived from natural sources, as natural substances are safer than manufactured pharmaceuticals. Therefore, this study investigated the inhibitory properties of mangiferin and friedelin against glucokinase (GK), dipeptidyl peptidase-IV (DPP-IV), α-amylase, and α-glucosidase using computational methods, in vitro enzyme assays, and in-depth ADMET analysis. The study utilized a computer-aided drug design approach to assess the potential therapeutic properties of mangiferin and friedelin as Type 2 diabetes mellitus (T2DM) therapeutic agents. Molecular docking studies’ outcomes encouraged the evaluation of both compounds in in vitro enzymatic assays. The docking study results were validated with the help of molecular dynamics simulation. Mangiferin and friedelin showed that they activated GK 20% and 5% more than the basal activity of the enzyme, respectively. In the DPP-IV enzyme assay, mangiferin and friedelin demonstrated IC50 values (74.93 ± 0.71 and 110.64 ± 0.21 µg/mL, respectively) comparable with the reference compound sitagliptin. Moreover, mangiferin and friedelin showed IC50 comparable to acarbose against α-amylase (9.72 ± 0.15, 11.84 ± 0.06, and 10.19 ± 0.05 mg/mL, respectively). In the α-glucosidase enzyme assay, mangiferin, friedelin, and acarbose displayed 11.72 ± 0.10, 14.34 ± 0.02, and 9.14 ± 0.06 mg/mL of IC50 values, respectively. The compounds showed promising in silico ADMET and drug-likeness properties, with potential binding affinities with all enzymes. In vitro enzymatic assays showed mangiferin and friedelin activated GK 20% and 5% more than basal activity, with IC50 values comparable to acarbose.