As pharmaceutical analysis progresses towards environmental sustainability, there is a growing need to enhance the safety and health conditions for analysts. Consequently, the incorporation of chemometrics into environmentally friendly analytical methods represents a promising approach. Favipiravir, cefixime, and moxifloxacin hydrochloride have been currently used in COVID-19 treatment. In this study, we develop spectrophotometric methods depending on chemometric based models to measure the levels of favipiravir, cefixime, and moxifloxacin hydrochloride in pharmaceutical preparations and spiked human plasma. It is challenging to determine favipiravir, cefixime, and moxifloxacin simultaneously because of overlap in their UV absorption spectra. Two advanced chemometric models, partial least square (PLS) and genetic algorithm (GA), have been developed to provide better predictive abilities in spectrophotometric determination of the drugs under study. The described models were created using a five-level, three-factor experimental design. The outcomes of the models have been thoroughly assessed and interpreted, and a statistical comparison with recognized values has been taken into consideration. The analytical eco-scale and the green analytical procedure index (GAPI) evaluation methods were also utilized to determine how environmentally friendly the mentioned models were. The outcomes demonstrated how well the models described complied with the environmental requirements.