Interfacially active lipases can be immobilized at a biphasic interface to enhance turnover recyclability and to facilitate product separation. Extensive coarse-grained molecular dynamics simulations of lipase A (LipA) from Bacillus subtilis show a bimodal orientational distribution of the enzyme at an oil–water interface, arising from its ellipsoidal Janus particle-like character. The relative orientational preference can be tuned by pH. The simulations rationalize a rare experimental observation of an order of magnitude increase in the turnover rate of this lipase upon its noncovalent tagging by a single surfactant molecule at the interface, compared to its rate in bulk water. The adsorption free energy, the interfacial activation, a decrease in the number of orientational fluctuations, and an increased rate of translational diffusion, to all of which the Janus character of LipA contributes, are the factors responsible for this enhancement. This study can spur further investigations of the Janus behavior of enzymes to enhance their activity as well as to stabilize the biphasic emulsion needed for interfacial catalysis.