Two different approaches were optimized for extraction of empagliflozin and metformin from spiked plasma samples. Liquid-liquid extraction technique was applied using diethyl ether. Good results were obtained for empagliflozin but liquid-liquid extraction failed to simultaneously extract metformin and empagliflozin from human plasma that may be attributed to the high hydrophilicity of metformin with relatively low Log P that diminishes its ability to migrate to the organic layer. Plasma sample was divided into two parts in order to optimize the extraction procedure for each drug using the most suitable method followed by combining them together again as one sample showing high recovery outcomes. Plasma sample preparation involved direct precipitation of plasma proteins to obtain supernatant contains metformin that was concentrated using vacuum evaporation and then it was added to the reconstituted other plasma part that contains empagliflozin after its liquid-liquid extraction and vacuum evaporation till dryness.