A new process design and operation for the extraction of polyphenols from fresh lettuce was developed. Microwave assisted centrifugation (MW/C) is a combination of microwave heating to explode the internal cells of biological material containing secondary metabolites, and centrifugation to intensify diffusion, collection and separation. MW/C is performed at atmospheric pressure without adding any solvent or water. A detailed study concerning optimization of different operating parameters like microwave power, centrifugal force and extraction time, was performed. MW/C has been compared not only to the reference conventional solvent extraction (CSE) technique but also to microwave extraction assisted by low rotational speed (MW/R) to assess the synergy between centrifugation force and microwave heating. Extracts obtained by MW/C, MW/R and CSE method were compared for the recovery of polyphenols at different time of the process in optimized operating conditions. The new combined MW/C process provided reduction in the extraction time compared to MW/R process, with an enhancement in recovery of target compounds. Energetic and environmental impacts using this combined process were evaluated in a scale up perspective.