Plants have been used for therapeutic purposes against various human ailments for several centuries. Plant-derived natural compounds have been implemented in clinics against microbial diseases. Unfortunately, the emergence of antimicrobial resistance has significantly reduced the efficacy of existing standard antimicrobials. The World Health Organization (WHO) has declared antimicrobial resistance as one of the top 10 global public health threats facing humanity. Therefore, it is the need of the hour to discover new antimicrobial agents against drug-resistant pathogens. In the present article, we have discussed the importance of plant metabolites in the context of their medicinal applications and elaborated on their mechanism of antimicrobial action against human pathogens. The WHO has categorized some drug-resistant bacteria and fungi as critical and high priority based on the need to develope new drugs, and we have considered the plant metabolites that target these bacteria and fungi. We have also emphasized the role of phytochemicals that target deadly viruses such as COVID-19, Ebola, and dengue. Additionally, we have also elaborated on the synergetic effect of plant-derived compounds with standard antimicrobials against clinically important microbes. Overall, this article provides an overview of the importance of considering phytogenous compounds in the development of antimicrobial compounds as therapeutic agents against drug-resistant microbes.