A new highly reactive isobutyl lactide monomer (IBL) was synthesized with the ring closing of halogenated carboxylic acid acquired by the reaction of (S)-2-hydroxy-4-methylpentanoic acid with 2-bromopropionyl bromide. A desired thermosensitive and injectable PEG-based poly(isobutyl lactide) di-and triblock copolymers (MePEG-PIBL and PIBL-PEG-PIBL), a promising alternative to customary PEG-based PLA and PLGA block copolymers, have been synthesized with narrow polydispersities as low as 1.08, high conversions up to 99%, and suitable hydrophilic/ hydrophobic balances for gel−sol applications by ring-opening polymerization at 120 °C. The polymerization rate of MePEG-PIBL was found to be the highest among other PEG-based substituted glycolides (MePEG-PDIBG, MePEG-PIPL, and MePEG-PDIPG) due to having a single and less hindered secondary β-carbon atom (R 2 CH 2 ) in IBL. The mechanism of poly(asymmetrical glycolide)s was also illuminated by single-frequency decoupled 1 H NMR, 13 C NMR, and optical rotation analyses by taking into account the effect of substituents on symmetrical and asymmetrical glycolides. PIBL units of the block copolymers showed an amorphous phase, critical for desired drug release rate, in thermal analyses. Thus, PIBL-based copolymer gels displayed a more effective release profile of paclitaxel (up to 57%) than semi-crystalline PLLA-PEG gels (up to 5.7%) in 2 weeks. The location of PEG, present as an internal or lateral component in copolymers, also affected the rate of hydrolitic degradation (34.6% vs 23.7% degradation of PIBL units in di-and triblock copolymers, respectively). According to the results of cell viability assays (WST-1 test and live/dead assay), where L929 and human primary dermal fibroblasts were tested, the triblock copolymer did not cause any cell damages or cell morphological changes in all concentration ranges tested (0.1−3.0 mg mL −1 ). The aqueous solutions of these copolymers exhibited very well temperature-dependent reversible gel−sol transitions for use in a localized drug delivery system.