Biodegradable aliphatic polyesters have been widely used in biomedical fields owing to their good biocompatibility. One big challenge is to precisely modulate their degradation rate and degradation products under physiological conditions. In this work, we designed and synthesized two types of poly(4-hydroxybutyric acid) derivatives that can quickly depolymerize via intramolecular cyclization into corresponding γ-butyrolactone derivatives under physiological conditions. The polymers were synthesized by the Passerini multicomponent polymerization of OEG-NC and ethyl ( E )-4-oxo-but-2-enoate, followed by hydrogenation. Nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) were used to follow the degradation of these polyesters under physiological conditions (pD 7.4 buffer solution, 37 °C). It was demonstrated that the molar mass of the polyester gradually decreased with time together with the increase of the amount of corresponding γ-butyrolactone derivatives as the only degradation product. After 1 d, 85% of the polyester was degraded. When the pH of the buffer was decreased to 6.8 or a mixture of buffer and acetone was used as the degradation media, the degradation was slowed down, but γ-butyrolactone derivatives are still the only degradation products, implying that increase of the medium polarity and pH can accelerate the degradation. Three small model molecules that mimic the polymer repeating unit, end group, and degradation product were synthesized and their hydrolysis were investigated under identical conditions. Based on these results, we confirm that under physiological conditions, no random degradation via hydrolysis of the polyester backbone occurred. The degradation mechanism was thus elucidated. The first step is the fast head-to-tail depolymerization of the polyester via intramolecular cyclization, forming γ-butyrolactone derivatives as the only products. Then, slow hydrolysis of γ-butyrolactone derivatives into 4-hydroxy butyrate occurred. This type of polyester is the first reported depolymerizable polyester with simple structure under physiological conditions. Our current efforts are end-capping these polymers with various stimuli-responsive functional groups to develop new self-immolative polymers that can be used in biomedical fields as drug carriers.