Type 2 diabetes mellitus (T2DM) is the most common type of diabetes mellitus. It is caused by decreased insulin sensitivity in target organs like liver, muscle and adipose tissue, and/or a deficiency in insulin secretion. In T2DM, increased hepatic glucose output and decreased glucose uptake by skeletal muscle cells are the principal contributors to the associated hyperglycemic state. The aim of this study was to assess the antidiabetic potential of five medicinal plant extracts using in vitro cell based assays targeting glucose uptake in C2C12 skeletal muscle cells [1] and glucose-6-phosphatase activity (G6Pase) [2] in rat hepatoma H4IIE. Cells were treated for 18h with maximal non-toxic concentrations (50 µg/mL) of the ethanolic extract of Psidium guajava (leaf and bark), Phyllanthus niruri (aerial parts), Eugenia jambolana (dried fruit) and Rhizophora mucronata (bark), which were determined by the lactate dehydrogenase (LDH) cytotoxicity assay. None of the extracts were able to reduce G6Pase activity. In contrast, one plant extract (P. guajava leaf extract) was found to significantly increase deoxyglucose uptake in C2C12 muscle cells (161%, p ≤0.001), to levels higher that of the positive control metformin (144%, p ≤0.05) and insulin (142% p ≤0.05) in comparison to the vehicle control (DMSO). In addition, the activity of extracts of P. niruri aerial parts and Eugenia jambolana dried fruit (both at 142%, p ≤0.05) was close to those of the positive controls. In conclusion, our results demonstrated that P. guajava (leaves), P. niruri (aerial parts) and E. jambolana (dried fruit) extracts improve muscle glucose uptake and may thus have potential applications in treatment of type 2 diabetes.