Two types of polyurethanes with alternating and random block architectures, hydroxyl-terminated liquid polybutadiene and poly(ethylene glycol) block copolymers (HTPB-alt-PEG and HTPB-co-PEG), were synthesized using a coupling reaction route between the hydroxyl groups and the isocyanate groups. The chemical and crystal structures were characterized using Fourier transform-infrared spectroscopy (FTIR) and X-ray diffraction, while phase behavior was examined using scanning electron microscopy (SEM) and differential scanning calorimetry. The biodegradation in a simulated human body fluid was investigated through mass loss, SEM, and FTIR. The experimental results indicated that all of the polyurethane samples bore the microphase separation structure, and the separation degree depended on the sequence structure and molecular weight (MW) of PEG and further affected their in vitro degradation. The driving force was related to the restricted movement of the molecular segments, the crystallization of the soft/hard phases, and/or the hydrogen bonding interactions between the hard segments. The surface morphological change of the degraded samples further demonstrated that the degradation became serious as the PEG MW increased and that the random block copolymers decomposed more easily than the alternating copolymers. The block polymer materials are expected to be incorporated into specific applications in related biomedical fields.