Bexarotene (BX), a selective retinoid X receptor agonist for cutaneous T-cell lymphoma, poses analytical challenges due to its extreme hydrophobicity and low aqueous solubility, requiring evaluation beyond traditional validation. This study comprehensively reviews chromatographic methods for BX determination over the past decades, evaluating them through the dual lenses of analytical performance and ecological sustainability. A systematic evaluation was conducted on existing methods using a suite of advanced green and blue chemistry metrics, including MoGAPI, AGSA, BAGI, CACI, RAPI, and GSST. These tools were applied to objectively compare the ecological footprints and practicality (RAPI) of various chromatographic approaches. The evaluation reveals that while LC-MS/MS techniques offer superior sensitivity and specificity for BX quantification, they frequently incur significant environmental costs. Most existing methods achieved only moderate greenness scores, highlighting a gap between analytical power and environmental responsibility. The inclusion of the RAPI tool further elucidated the practical challenges associated with these high-sensitivity methods. This review underscores the importance of balancing analytical rigour with ecological impact. It provides a strategic framework for selecting methods based on specific application needs and calls for future research into miniaturized separation techniques and green solvents to advance sustainable BX determination.