The ecological impact of routine quality control activities in the pharmaceutical industry is crucial, producing large amounts of dangerous organic waste. For that, the use of mixed-micellar LC was found beneficial. When sodium dodecyl sulfate (SDS) is mixed with Brij-35 as surfactants in the mobile phase, no organic modifier was needed for enhancing the analytes' elution time or resolution. In the proposed study, five antidiabetic drugs belonging to different antidiabetic classes; namely metformin (MTF), glibenclamide (GBC), gliclazide (GCZ), linagliptin (LNT) and dapagliflozin (DPF), have been studied using organic-solvent free Micellar RP-HPLC technique. The combination of double or even triple antidiabetic therapies from different classes is common and was proved efficient for the control of type-2 diabetes. The optimal mobile phase was composed of 0.12 M SDS, 0.008 M Brij-35 and 0.15 M triethylamine in water, adjusted to pH 4.5. The flow rate was set at 1.5 mL min −1 on RP-monolithic column (100 × 4.6 mm). Photodiode array detection was set at wavelength 245 nm for MTF and 225 nm the other analytes. Linearity ranges were 50–600 μg mL−1 for MTF, and 5–60, 2.5–30, 7.5–60, and 2.5–30 μg mL−1 for DPF, LNT, GCZ and GBC, respectively (R2 ≥ 0.997). Trueness and precision have been established across the specified ranges with recovery percentages range 98–105% and relative standard deviation of the results less than 2.5%. The obtained results of resolution, peaks’ symmetry and theoretical plates for the drugs under study proved the analytical capability of using mixed-micellar mobile phases for elimination of the organic-solvents without affecting the separation efficiency.