Antidepressant drugs, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are known to induce sexual dysfunction as a side effect. Duloxetine (DLX) and Tadalafil (TDL) are simultaneously determined in their pure state and laboratory-prepared mixtures by two novel, environmentally friendly, and accurate spectrophotometric methods. The first method based on second order derivatives while the second method is based on first derivative dual-wavelength detection. In method I, the linearity range was found to be 0.5-9 μg/mL and 1-14 μg/mL with limit of detection 0.15 μg/mL and 0.23 μg/mL for DLX and TDL, respectively, with a good correlation coefficient of 9998. In method II, the linearity range was found to be 1-10 μg/mL and 1-12 μg/mL with limit of detection 0.25 μg/mL and 0.20 μg/mL for DLX and TDL, respectively, with a good correlation coefficient of 0.9997 for DLX and 0.9998 for TDL. The validation of these methods followed the guidelines set by the International Council for Harmonization (ICH). The methods are accurate and precise. The proposed methods can be used for simultaneous determination of DLX and TDL in synthetic mixture. Additionally, the suggested method's greenness was assessed by means of four up-to-date ecological tools, namely the Eco-Scale, the National Environmental Method Index (NEMI), the Green Analytical Procedure Index (GAPI), and the Analytical Greenness metric approach and software (AGREE). The sustainability characteristics of the proposed method were also assessed using the Blue Applicability Grade Index (BAGI), a recently developed metric for assessing the practicality (blueness) of procedures.