The activity of lipase was inhibited or promoted by different macromolecular colloids, but the underlined general rules were not clear. In this paper, lipase activity was systematically analyzed in different macromolecular media. The detailed factors that affect the enzyme activity were extracted for quantification. Three functions, including viscosity, the crowding effect, and soft interactions, were established to describe the macromolecular medium effect. The medium parameter based on the Huggins constant and Kramer constant was able to characterize the quality of the macromolecular media. A multivariate nonlinear regression model was proposed for the correlation or prediction between three groups of factors and enzyme activity, and a crowding enzyme factor