Antibiotic resistance is a growing public health threat that complicates the treatment of infections. β-Lactamase enzymes, which hydrolyze the β-lactam ring present in many common antibiotics, are a major cause of this resistance and are produced by a broad range of bacterial pathogens. Here, we developed hydrogels that degrade specifically in the presence of β-lactamases and β-lactamase-producing bacteria as a platform for bacteria-triggered drug delivery. A maleimide-functionalized β-lactamase-cleavable cephalosporin was used as a crosslinker in the fabrication of hydrogels through end-crosslinked polymerization with multiarm thiol-terminated poly(ethylene glycol) macromers via Michael-type addition. We demonstrated that only hydrogels containing the responsive crosslinker were degraded by β-lactamases and β-lactamase-producing bacteria and in an porcine skin infection model. Fluorescent polystyrene nanoparticles, encapsulated in the hydrogels as model cargo, were released at rates that closely tracked hydrogel wet mass loss, confirming β-lactamase-triggered controlled cargo release. Nonresponsive hydrogels, lacking the β-lactam crosslinker, remained stable in the presence of β-lactamases and β-lactamase-producing bacteria and exhibited no change in mass or nanoparticle release. Furthermore, the responsive hydrogels remained stable in non-β-lactamase enzymes, including collagenases and lipases. These hydrogels have the potential to be used as a bacteria-triggered drug delivery system to control unnecessary exposure to encapsulated antimicrobials, which can provide effective infection treatment without exacerbating resistance.