In the current study, glycerol was successfully employed as a nonvolatile, non-toxic, non-flammable, biodegradable, very cheap, easily accessible, and efficient reaction medium for the microwave-enhanced diastereoselective synthesis of 2-(N-carbamoylacetamide)-substituted 2,3-dihydrothiophenes via a catalyst-free one-pot four-component reaction. A versatile range of starting materials were used, and diverse products were obtained in good to excellent yields and very short reaction times. Moreover, the reaction medium was recovered and reused several times without any loss of the efficiency.