<p>The aim of this study is to develop and validate UV spectrophotometric and RP-HPLC methods for the simultaneous quantification of empagliflozin and losartan in a synthetic fixed-dose combination. In addition to method validation, a sustainability and complexity assessment was performed to support method selection for routine pharmaceutical analysis. The UV method is based on a Q-absorbance ratio approach using 225 and 239.20 nm, while the HPLC method employed a C18 column with a mobile phase of orthophosphoric acid buffer (pH 3.0) and acetonitrile (50:50, v/v), at a flow rate of 1.0 mL/min with detection at 217 nm. Both methods were validated according to ICH Q2(R2) guidelines. Further evaluation was conducted using the blue applicability grade index (BAGI) and click analytical chemistry index (CACI) to assess greenness and procedural efficiency. Both methods demonstrated excellent linearity (<i>r</i>² &gt; 0.996), precision (%RSD &lt; 2), and recovery within the acceptable range of 98–102%. The UV method achieved good scores in environmental sustainability (BAGI = 82.5) and practical simplicity (CACI = 74) compared to the HPLC method (BAGI = 72.5, CACI = 77). The assay results confirmed the accuracy of both methods for simultaneous estimation of empagliflozin and losartan without interference from excipients. The developed UV spectrophotometry and RP-HPLC methods are found to be accurate, precise, and suitable for routine estimations of empagliflozin and losartan in bulk and laboratory-prepared mixtures. The greenness assessments of developed methods further support the UV method as a more sustainable and efficient choice, while the HPLC method remains preferable where greater sensitivity or automation is required.</p>