Hybrid crosslinked hydrogel-based drug delivery systems can deliver therapeutically beneficial drug release effects through controlled release on a temporal and spatial scale. Due to their tuneable physicochemical properties and the ability to prevent drug degradation, these systems facilitate different physicochemical interactions that control drug release. This research aims to synthesize a potent pH-sensitive crosslinked chitosan/polyvinylpyrrolidone hydrogel using different ratios of both the polymers and varying the glutaraldehyde crosslinking agent amount by the solution casting technique for controlled amoxicillin-release properties to mitigate gastrointestinal tract bacterial infection. The effect of polymer ratios and glutaraldehyde amount is investigated by the developing porosity, gel fraction, and extent of swelling in simulated physiological fluids of pH 1.2, 6.8, and 7.4 and in vitro biodegradation at pH 7.4. Interaction between the polymers with the formation of crosslinked structures, good stability, amorphous phase nature, and honeycomb-like structures of the hydrogels is revealed by Fourier-transform infrared spectroscopy, thermogravimetric analysis, X-ray diffraction, and scanning electron microscopy. Based on these properties, a chitosan/polyvinylpyrrolidone hydrogel (ratio of 60:40) crosslinked with 600 μL glutaraldehyde in 8 g of the polymers displaying adequate swelling in acidic to basic pH and in vitro biodegradation at pH 7.4 is chosen for the in situ loading of 200 mg of the drug amoxicillin. The cumulative drug release in simulated physiological fluids and the drug release kinetics using different models show that the best-fit Korsmeyer-Peppas model suggests amoxicillin release from the matrix follows diffusion and swelling-controlled time-dependent non-Fickian transport related to hydrogel erosion. This composition displays excellent antimicrobial activity against Streptococcus pyogenes and Escherichia coli.