A new class of biodegradable crosslinked hydrogel, consisting of hydrophobic polylactic acid (PLA) and hydrophilic dextrin in presence of crosslinker N,N-methylene bisacrylamide (MBA) has been synthesized by free-radical polymerization technique using potassium persulfate (KPS) as initiator. By variation of crosslinker concentration, a series of hydrogels have been prepared and the optimized grade has been selected on the basis of higher crosslinking efficiency as well as lower equilibrium swelling characteristics, XRD analysis. The hydrogels have been characterized by FTIR spectra, 13C-NMR spectra, CHN analysis, SEM analysis, swelling characteristics, and toxicity study. In vitro release study of model drugs (ciprofloxacin and ornidazole) from hydrogel matrix has been performed in various buffer solutions at 37°C. The drug release kinetics and mechanism have been studied using zero order, first-order kinetic models, Korsemeyar–Peppas model, Higuchi model, Hixson–Crowell model, and nonlinear Kopcha model. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40039.