We present a comprehensive investigation on the interaction of tetronics (T1304 and T1307) with some important physiological salts (NaH2PO4, KH2PO4, Na2CO3, NaCl, and KI). Thermodynamic and microstructural aspects of these interactions were studied as a function of the solution temperature, pH and salt concentration. Characterizations were performed using turbidimetric, calorimetric, and scattering techniques. We show that, at ambient temperature, T1304 molecules aggregated to form spherical core-shell aggregates displaying a unimodal distribution pattern. On the other hand, unimers and large clusters dominated in the case of highly hydrophilic T1307. Its micellization was promoted in the presence of salts as per the following trend: NaCl < KH2PO4 < NaH2PO4 ≪ Na2CO3. Aggregation was found to be endothermic, and hydrophobic interactions (TΔSmic > ΔHmic) prevailed. The enthalpy-entropy compensation plot was found to be linear for both copolymers. Demicellization occurred in the presence of KI as it facilitated the buildup of water structures around the copolymer chains. This could be verified from the increase in the cloud point, critical micelle concentration, and free energy. Overall, the temperature and salts inflicted a stronger hydrophobic effect upon T1304 in comparison to T1307.