Doxorubicin (DRB) is an anthracycline oncogenic drug extracted from cultures of Streptomycespeucetius var. caesius. It is frequently recommended as an anti-neoplastic agent for the treatment of diverse malignancies. It exerts its antineoplastic effect either via inhibiting the enzyme topoisomerase II and/or via intercalation to DNA or reactive oxygen species generation. In the present article, the direct, simple, one-pot, somewhat eco-safe, and non-extractive spectrophotometric system was executed to track doxorubicin, a chemotherapeutic remedy, in the presence of paclitaxel, a naturally occurring Taxan antineoplastic radical, through the greenness rated method. DRB’s optical density was studied in various mediums and solvents to develop the current approach. An acidic ethanolic solution was found to increase the optical density of the sample significantly. At 480 nm., the most remarkable optical density was obtained. Various experimental factors, including intrinsic media, solvent, pH, and stability time, were investigated and controlled. The current approach achieved linearity within the 0.6–40.0 µg mL-1 range, accompanied by a limit of both detection and quantification (LOD and LOQ) of 0.18 and 0.55 µg mL-1, correspondingly. The approach was validated under the ICH guidelines (Quality Guidelines). The system’s greenness and enhancement degree were estimated.