An aliphatic poly(ester-ether) with methoxy side chains from a glycerol derivative that exhibits increased hydration properties for potential applications in blood-contacting medical devices is developed. The poly(ester-ether) is prepared by ring-opening polymerization (ROP) of an analogue of 1,4-dioxan-2-one (DX) with a methoxy-containing substituent in the presence of acidic organocatalysts. It is found that the ring-chain equilibrium resides in the ROP of the DX analogue at room temperature and at relatively low monomer concentration (≈2 m). The organocatalytic ROP has enabled more than 80% monomer conversion at temperatures below 0 °C in the bulk state. The methoxy-bearing poly(ester-ether) is insoluble in water, amorphous, and viscous, demonstrating a high level of interaction with water when evaluating the thermal properties of the hydrated polymer and water contact angles. The polymer also shows susceptibility to hydrolysis and end-group dependence on thermal degradation. These results suggest a good potential for methoxy-bearing poly(ester-ether) as a biodegradable and biocompatible polymer derived from renewable feedstocks.