Lignin is a promising starting material for the future provision of aromatic platform chemicals. Its low solubility in aqueous media, however, hampers its efficient depolymerization using enzymatic approaches. Thus, the addition of cosolvents is often required to improve lignin solubility. Herein, we demonstrate that mixtures of ethylene glycol:choline chloride (EG:ChCl)-based deep eutectic solvents (DES) and glycine buffer represent powerful solvent systems for lignin dissolution in β-etherase-catalyzed lignin depolymerization reactions. They enabled the use of high lignin concentrations (up to 30 g L-1 at 60 % v/v DES) without abolishing enzyme activity. While EG:ChCl 2:1 proved superior in solubilizing lignin, the highest volumetric yield of the desired monoaromatic depolymerization products guaiacylhydroxypropanone and syringylhydroxypropanone was achieved using 20 g L-1 lignin and 50 % v/v EG:ChCl 4:1. Moreover, detailed MD analyses on the interactions of the lignin model compound guaiacylglycerol-β-guaiacyl ether (GGE) and the solvent mixture, including also glycine as buffer component, highlight the importance of EG and glycine for lignin solubility, while the ratio of EG and ChCl in the DES impacted the solvation structure and dynamics of GGE in the solvent mixture. Thus, our comprehensive study offers insights into the molecular determinants that affect lignin solubility and its enzymatic depolymerization.