Etravirine (ETR) is a heterocyclic diarylpyrimidine derivative with the following chemical name 4-([6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy)-3,5-dimethylbenzonitrile. Complex chemical structures with nitrogen and oxygen atoms create chemical reactivity as well as specificity in the binding. Advanced chromatographic techniques must be used for correct quantification and stability analysis during pharmaceutical applications. By lowering the use of organic solvents and following strict validation guidelines, a novel reverse-phase high-performance liquid chromatography method for ETR was developed and validated as effective, dependable, and environmentally friendly. An isocratic eluting method was developed using acetonitrile and buffer (25 mM potassium dihydrogen phosphate in water) at a ratio of 30:70 (%v/v) with a flow rate of 1.0 mL/min in a Kromasil C18 column at 310 nm. It was found to be linear around 1.50–10.50 μg/mL, with a r2 value of 0.9994. The AGREE tool for evaluating greenness resulted in a score of 0.57, and another tool called the analytical method greenness scored 839.17 and ensured the greenness of the method. The developed method is simple, sensitive, precise, accurate, robust, and reproducible for the analysis of ETR in bulk and tablet formulations for routine analysis. © 2025 Elsevier B.V., All rights reserved.