The mode of interaction of surfactant with drug remains a keen interest in the research area owing to the improvement of drug carrier systems in the therapeutic formulations. In order to investigate the drug-surfactant interactions, phase separation, UV-visible spectroscopic studies, and molecular dynamics simulation were employed. The phase partitioning behavior (in aq. Na2SO4, Na3PO4, and sodium dodecyl sulfate (SDS)), micellization, as well as molecular dynamics simulation of the grouping of triton X-100 (TTX-100) and antidiabetic drug metformin hydrochloride (MMH) have been examined. The CP values of TTX-100 + MMH system have been detected to be lessened with the growing concentration of Na2SO4 and Na3PO4, where the CP values follow the order: CP (aq. Na3PO4) < CP (aq. Na2SO4). The introduction of SDS caused the enhancement of CP for the study system. The critical micelle concentration (CMC) for the TTX-100 + MMH mixture were determined using the absorbance vs. log [TTX-100] plot using the UV-Visible spectroscopic tool. The CMC values were attained to be heightened with the rising content of MMH and thus, the presence of MMH disfavors the micelle growth of TTX-100. The free energy changes of clouding (△G0c) and micellization (△G0b)  have been noticed as positive (nonspontaneous process) and negative (spontaneous process), respectively. The changes in standard enthalpy (△H0c), entropy (△S0c), thermodynamic transfer parameters (△G0c,tr , △H0c,tr , △S0c,tr ), and the △H0c - △S0c compensation factors were also computed and appropriately explained. The values of  △H0c  and  △S0c  recommend that the clouding of TTX-100 + MMH in aq. Na2SO4 and Na3PO4 is controlled by enthalpy alone, while the process is controlled by entropy in aq. SDS solution. In this process, the electrostatic interactions and hydrophobic force are recommended as core forces among the employed media. By applying the molecular dynamics simulation, the atomic-scale interactions between MMH and TTX-100 were unveiled, showing a strong correlation with the experimental outcomes.