With the aim of developing polymers having controlled thermoplasticities and biodegradabilities, a series of cellulose ester–graft–polylactide copolymers was synthesized using a homogeneous one-pot system in which the reaction medium was the ionic liquid 1-ethyl-3-methylimidazolium diethylphosphate (EmimDEP). The structures and compositions of the copolymers were controlled by varying the feed ratio of the carboxylic anhydride (acetic (C2), propionic (C3), or hexanoic (C6)) and L-lactide. In terms of side-chain substitution, the copolymers exhibited DSAcyl values of 0.7–2.7 and MSPLA values of 3.2–14.2. With increasing DSAcyl, the copolymers presented enhanced thermal stability and thermoplasticity due to the intermolecular interactions between the acyl groups and polylactide side-chains. The effect of graft-chain composition on mechanical properties and biodegradability was investigated using homogeneous cast films prepared with the copolymers. The mechanical properties were found to be affected by the carbon number of the acyl group (C2–C6), with higher carbon numbers imparting better plasticization. To investigate biodegradability, a two-step enzymatic degradation was performed using proteinase K and then cellulase. The copolymers with DSAcyl values below 1.3 exhibited enzymatic biodegradability with weight losses in the range 15.2%–34.6% (cf. 58.4% for polylactide).