The nanozymes are nanomaterials that simulate the performance of enzymes; they have become an attractive antimicrobial agent because of their stability, fabrication, and affordability over natural enzymes. Nanozymes are, however, ineffective when administered, and thus a smart delivery system is needed to maximize bioavailability, specificity, and efficacy of therapeutics. In this chapter, the principles and the challenges of nanozyme delivery, different approaches, e.g., nanocarriers, surface modifications, and the stimuli–responsive mechanisms, and recent advances, are discussed. It is important to design the delivery systems that can reach the complex biological environment, providing the nanozyme functionality. The encapsulation of liposomes and polymeric nanoparticle biocompatible nanocarriers increases stability and specific controlled release of infection sites. Targeting ligands or stealth coatings that modify the surface can increase specificity and minimize off-target effects. To enhance therapeutics accuracy, stimuli-sensitive systems that induce nanozyme activation to altering environmental cues (ex: pH or enzymes) are investigated. A combination of smart technologies like biosensors and real-time surveillance has presented additional opportunities to improve nanozyme delivery. These innovations are meant to fill the gap between laboratory research and clinical application by addressing issues, such as scalability, safety, and regulatory compliance. This chapter highlights the necessity of joint research and technological development to break down those barriers so that the clinical translation of nanozyme-based antimicrobial therapies, among other approaches, can proceed faster.