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The applications of surfactants and drugs in a wide variety of fields such as pharmaceuticals, food industry, textile, fabrics, etc. are increasing significantly. Herein, we investigated the clouding behavior and thermodynamics of triton X-100 (TX-100) and metformin hydrochloride (MNH) drug mixture in the effect of several polyols and polyethylene glycol (PEG) polymer. The phase separation behavior of the mixture of TX-100 + MNH has been deduced with the help of the cloud point technique. The cloud point (CP) values for the TX-100 and drug mixtures were documented in a decreased and increased manner with the augmentation of the concentration of polyol and PEG respectively. With the subsequent enhancement of polyol and PEG content, the CP values were recorded in the following order: $ \textrm{C}{\textrm{P}_{{\textrm{H}_2}\textrm{O} + \textrm{PEG }}} \gt \textrm{C}{\textrm{P}_{{\textrm{H}_2}\textrm{O} + \textrm{fructose}}} \gt \textrm{C}{\textrm{P}_{{\textrm{H}_2}\textrm{O} + \textrm{glucose}}} \gt \textrm{C}{\textrm{P}_{{\textrm{H}_2}\textrm{O} + \textrm{galactose}}} \gt \textrm{C}{\textrm{P}_{{\textrm{H}_2}\textrm{O} + \textrm{maltose}}} $ C P H 2 O + PEG > C P H 2 O + fructose > C P H 2 O + glucose > C P H 2 O + galactose > C P H 2 O + maltose . The standard enthalpy change ( $ \Delta H_c^o $ Δ H c o ) and entropy change ( $ \Delta S_c^o $ Δ S c o ), of TX-100 + MNH mixture in aq. polyols solutions were documented as negative; the negative values reduce in magnitudes with the polyols contents and become positive at the highest polyol content while opposite trend was obtained in presence of PEG. The presence of electrostatic and hydrophobic interactions among TX-100/MNH/polyols/polymer has been recommended as the interaction forces. [ABSTRACT FROM AUTHOR]