Secondary metabolites are organic substances produced by various living organisms (e.g., bacteria, fungi, plants, animals) that do not have any direct influence in the normal physiological growth, development, and reproduction of the organism. Secondary plant metabolites serve as the scientific foundation for the utilization of various herbs in traditional medicine as they have been labeled as antibacterial, antifungal, and antiviral and hence safeguard plants from their invasion. Plants synthesize a wide range of these secondary metabolites as an adaptation of self-defense and communication systems with other organisms living in their corresponding environment. They have got a wide array of applications in various diseases including diabetes, Alzheimer’s disease, several cancers, fever, hypotension, and peptic ulcer. They have also been discovered to be excellent candidates for anti-inflammatory and antimicrobial activities. The hunt for novel antimicrobial compounds from nature has escalated since the emergence of antibiotic resistance as a crucial public health concern. To confront bacteria that are resistant to antibiotics, there have been a growing number of studies in recent years to find new bioactive substances with a plant origin. Emerging multidrug-resistant (MDR) pathogens, often known as “ESKAPE” organisms, pose a significant threat to public health today on a global scale. These include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. This book chapter will concentrate on the classification and discussion of the major and minor groups of secondary plant metabolites with their widespread application in eradicating various human diseases and will also cover the major concern of using plant-derived secondary metabolites as antimicrobials as opposed to the available antibiotics in the international market.