Population of the world run into several health-related emergencies among mankind and humans as it creates a challenge for the evolution of novel drug discoveries. One such can be the emergence of multidrug-resistant (MDR) strains in both hospital and community settings, which have been due to an inappropriate use and inadequate control of antibiotics that has led to the foremost human health concerns with a high impact on the global economy. So far, there has been application of two strategies for the development of anti-infective agents either by classical antibiotics that have been derived for their synthetic analogs with increased efficacy or screening natural compounds along with the synthetic compound libraries for the antimicrobial activities. However, need for newer treatment options for infectious diseases has led research to develop new generation of antimicrobial activity to further lessen the spread of antibiotic resistance. Currently, the principles aim to find novel mode of actions or products to target the specific sites and virulence factors in pathogens by a series of better understanding of physiology and molecular aspects of the microbial resistance, mechanism of infection process, and gene-pathogenicity relationship. The design various novel strategies tends to provide us a path for the development of various antimicrobial therapies that intends to have a broader and wider antimicrobial spectrum that helps to combat MDR strains worldwide. The development of antimicrobial peptides, metabolites derived from plants, microbes, phage-based antimicrobial agents, use of metal nanoparticles, and role of CRISPR have led to an exceptional strategies in designing and developing the next-generation antimicrobials. These novel strategies might help to combat the seriousness of the infection rates and control the health crisis system.