Tetrafluoropropene (R1234yf) is the most likely replacement for tetrafluoroethane (R134a), a widely used refrigerant, propellant, and solvent, characterized by a very high global warming potential. In this study, solvation properties of R1234yf were studied experimentally and computationally for solubility of artemisinin, a precursor to the important biopharmaceutical API, and extraction of artemisinin from biomass. R1234yf was shown to be a poorer solvent than R134a for artemisinin. COSMO-RS calculations of solvation in R1234yf suggest that the decrease in performance is likely due to entropic effects. However, R1234yf was effectively used in solid–liquid extraction of Artemisia annua. The new solvent has shown an increased selectivity to the target metabolite artemisinin. This should allow for design of more selective separation processes based on the new solvent molecule with a low global warming potential of 4 relative to CO2.