Abstract Lipase-catalyzed Knoevenagel condensation of a ketone/aldehyde (e.g., benzaldehyde 1) and the active hydrogen compound (e.g., ethyl cyanoacetate 2 or malononitrile 3) is often regarded as catalytic promiscuity. The alternative mechanism suggests partial enzymatic hydrolysis of 2, whereupon the products initiate fusion 1 + 2. Three lipases (porcine pancreatic, Mucor javanicus and Yarrowia lipolytica) did not hydrolyze 2, but significantly accelerated condensations 1 + 2 and 1 + 3 (3 is not hydrolyzable), thereby corroborating promiscuous enzymatic activity. Main conversion took place within the active site (based on competitive inhibition by caffeic acid). Yet, the “active” Ser residue of lipases was unimportant, because its covalent modification did not affect condensation. The reaction (particularly 1 + 3 condensation) was to some extent promoted by unspecific residues of lipase, as well as albumin and simple proton acceptors. Spontaneous condensation in water/ethanol surprisingly revealed kinetics with substrate saturation. We explained this depart from linearity by a two-step steady state mechanism including deprotonation of the active hydrogen substrate 3H by polar solvent, followed by direct collision of a temporary complex solvent ·H+·3– with 1. Similar mechanism with a more sophisticated binding of substrates was conjectured for the lipases.