In the search for novel drugs for health preservation, the active ingredients of medicinal herbs have been used since time immemorial. Liquorice, a potent medicinal herb derived from the root and rhizomes of Glycyrrhiza species, has been used worldwide for the treatment of various diseases. A number of compounds have been isolated from the liquorice root, including retrochalcones, viz. echinatin, licochalcone A, B, C, D and E, having a diverse range of pharmacological applications such as antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, anti-diabetic, anti-obesity, anti-parasitic, to name a few. This review highlights the different synthetic procedures for retrochalcones and their in vitro, in vivo, ex vivo and in silico studies, along with the underlying molecular mechanisms. In addition, the total syntheses of licochalcone F and H, the regioisomers of licochalcone E and C, respectively, have also been included. Herein, the maximum possible biological applications of retrochalcones cited so far in the literature have been reviewed. The insights from this review will further advance the role and application of retrochalcones in the field of medicinal chemistry.