pH-Responsive polymers have great potential in biomedical applications, including the selective delivery of preloaded drugs to tissues with low pH values. These polymers usually contain acid-labile linkages such as esters and acetals/ketals. However, these linkages are only mildly pH-responsive with relatively long half-lives (t1/2). Orthoester linkages are more acid-labile, but current methods suffer from synthetic challenges and are limited to the availability of monomers. To address these limitations, a sugar poly(orthoester) was synthesized as a highly pH-responsive polymer. The synthesis was achieved by using 2,3,4-tri-O-acetyl-α-D-glucopyranosyl bromide as a difunctional AB monomer and tetra-n-butylammonium iodide (TBAI) as an effective promoter. Under optimal conditions, polymers with molecular weights of 6.9 kDa were synthesized in a polycondensation manner. The synthesized glucose poly(orthoester), wherein all sugar units were connected through orthoester linkages, was highly pH-responsive with a half-life of 0.9, 0.6, and 0.2 hours at pH 6, 5, and 4, respectively.