A study of the retention behavior of four frequently prescribed anti-inflammatory 2-arylpropionic acid derivatives on a reversed-phase thermostable stationary phase was conducted. Extra-thermodynamic investigations were carried out over the temperature range of 303–338 K. A modified van’t Hoff analysis was applied to assess the enthalpy, entropy, and Gibb’s free energy changes that take place during the mass transfer from the mobile phase to the stationary phase. It has been proven that enthalpy–entropy compensation exists as an extra-thermodynamic relationship. The effect of molecular structures of the investigated drugs on thermodynamic and retention behaviors was also explored. A validated high-temperature liquid chromatography method was established for the separation and analysis of ketoprofen, naproxen, diclofenac, and ibuprofen in pharmaceutical formulations and human urine with %recoveries within the range of 90.1–105.6 % and standard deviation not exceeding ±4.1% in all cases. The developed method greenness was positively assessed by the analytical eco-scale score tool.