A simple and efficient method was developed for the synthesis of 2,20-arylmethylene dicyclohexane-1,3-dione derivatives via the Knoevenagel–Michael cascade reactions of aromatic aldehydes and 1,3-cyclic diketones catalyzed by ‘‘Amano’’ lipase DF, which expands the application field of enzyme catalytic promiscuity. This protocol provides several advantages over the traditional chemical synthesis, such as simple work-up procedure, high yields(up to 94%) and environmental friendliness. A simple and efficient method was developed for the synthesis of 2,20-arylmethylene dicyclohexane-1,3-dione derivatives via the Knoevenagel-Michael cascade reactions of aromatic aldehydes and 1,3-cyclic diketones catalyzed by ’’ Amano ’’ lipase DF , which expands the application field of enzyme catalytic promiscuity. This protocol provides several advantages over the traditional chemical synthesis, such as simple work-up procedure, high yield (up to 94%) and environmental friendliness.