Tuning the molecular interaction between enzymes and their solvent environment through polymer modification can greatly improve activity and thus utility in biocatalytic reactions. In this work, this approach was exploited to enhance the activity of lipase A (LipA) from Bacillus subtilis in anhydrous ionic liquids (ILs), which are highly attractive solvents for biocatalysis. Specifically, we showed that the transesterification activity of LipA in anhydrous 1-butyl-3-methyl imidazolium hexafluorophosphate ([BMIM] [PF6]) was improved up to 19-fold via covalently conjugating the enzyme with the IL-soluble polymer poly(4-acryloylmorpholine) (PAcMO). The increase in transesterification activity correlated with an increase in LipA solubility in [BMIM] [PF6] as well as, notably, the number of conjugated PAcMO repeat units. Light scattering results further showed that the attachment of PAcMO disrupted the aggregation of LipA in aqueous buffer, which was used as a proxy to understand the mechanism of activation of LipA in the IL, where aggregation was more pronounced. Additionally, using static light scattering, the Flory-Huggins interaction parameter (chi) for the polymer-IL interactions was determined (0.457). The favorable PAcMO-IL interactions presumably compensated for the unfavorable interactions between the enzyme and IL, which resulted in the improvement in dissolution and, in turn, activity due to reduced diffusional limitations. Through rationally considering x, a similar approach may be used to tune the molecular interaction between other enzymes and ILs with other polymers, which has widespread implications for the enhancement of biocatalysis in ILs.