Abstract: Processing parameters for heat reflux and ultrasonic-assisted extraction techniques were optimized. Optimal operating conditions, extraction solvents and extraction yields for both methods were established. Although methanol showed high extraction efficiency in heat reflux extraction, residual amounts of methanol caused adulteration of extracts. To circumvent this drawback, a novel ultrasonic-assisted aqueous extraction process was optimized and orthogonally designed to pave the way for replacing the toxic organic solvent, methanol with water. A new approach which utilizes fractional volumes of an extraction solvent was developed to minimize solvent consumption, improve chlorogenic acid solubility in water and enhance its aqueous extraction from dried tobacco leaves. Desired trajectories for the new ultrasonic assisted aqueous extraction process were found.