The rise of chronic and acute infections has increased reliance on antimicrobial agents. However, conventional antimicrobials often fail to deliver optimal therapeutic outcomes due to limitations such as low bioavailability, poor biocompatibility, nonspecific targeting, drug-induced toxicity, and the growing issue of antimicrobial resistance. Therefore, the concept of a resistance-proof antimicrobial agent (RPAA) and its smart delivery was introduced to overcome the existing problem and a targeted delivery due to the specific properties, such as: high bioavailability, biocompatibility, low drug-induced toxicity, biodegradability, high binding capacity with the pathogen, multiple targeting delivery, etc. This system generates a positive impact and could quash the multidrug resistance problem. In this review, we discuss: the rationale for developing a nanoengineering-based smart-delivery system for RPAA, the advantageous properties of such a system, the possible mechanism of delivery, and challenges in the development of a nano-drug delivery therapeutics tool for RPAA delivery as a solution to combat the global problem of drug resistance. We emphasize the urgent need for the development of such a next-generation drug delivery system and discuss the opportunities/hurdles as well as the questions that remain to be addressed. The article is important because it sheds light on the properties of nanoengineered drug delivery that could initiate new ways of thinking about the development of future-generation delivery systems. The article shares a promising idea that would be an essential foundation for opening a new window in the field of drug discovery and development of the smart delivery system for RPAA.