Nebivolol and valsartan (VAL) in combination with each other successfully control blood pressure and improve hypertension patient outcomes. To develop and validate innovative, simple, and sustainable spectrophotometric methods for the simultaneous analysis of nebivolol and valsartan. The new modified difference amplitude modulation (MD-AM) method uses only unified regression equation and does not require any resolution techniques. Other different approaches were also applied for the determination of the same mixture including univariate and multivariate spectrophotometric methods. The multivariate methods were PLS and PCR, whereas the univariate methods were derivative ratio (DD1), ratio difference (RD), constant center (CC), constant center spectrum subtraction (CC-SS), constant value coupled with amplitude difference (CV-AD), advanced concentration value (ACV), and amplitude difference (AD). The proposed methods use a green solvent; thus, the environmental impact of the presented procedures was evaluated qualitatively and quantitatively using six well-known evaluation tools. All methods were applied successfully for the analysis of the studied drugs in their bulk powder, pharmaceutical dosage form Byvalson®, and in vitro release at intestinal pH (7.4) using a USP dissolution tester. Results obtained were compared statistically with the reported method and with each other using a one-way ANOVA statistical test, and no significant differences were found. All green and white analytical chemistry evaluation tools results confirm the safety, sustainability, and cost-effectiveness of the approaches, indicating that the methods are regarded green and sustainable. Results were agreeable, encouraging their applicability in quality control laboratories for dosage form and making these methods an eco-friendly substitute for the analysis of this combined dosage form and for evaluating the dissolution profile. For the first time, a severely overlapped spectrum was determined using a unified regression equation without the need of extended part or zero contribution regions by the novel method MD-AM. The proposed methods are the first study of in vitro dissolution profiling of nebivolol hydrochloride (NEB) and VAL and the first sustainable and green methods applied without compromising the analytical criteria.