Microorganisms evolve resistance to antibiotics as a function of evolution. Antibiotics have accelerated bacterial resistance through mutations and acquired resistance through a combination of factors. In some cases, multiple antibiotic-resistant determinants are encoded in these genes, immediately making the recipient organism a “superbug”. Current antimicrobials are no longer effective against infections caused by pathogens that have developed antimicrobial resistance (AMR), and the problem has become a crisis. Microorganisms that acquire resistance to chemotherapy (multidrug resistance) are a major obstacle for successful treatments. Pharmaceutical industries should be highly interested in natural product-derived compounds, as they offer new sources of chemical entities for the development of new drugs. Phytochemical research and recent experimental advances are discussed in this review in relation to the antimicrobial efficacy of selected natural product-derived compounds as well as details of synergistic mechanisms and structures. The present review recognizesand amplifies the importance of compounds with natural origins, which can be used to create safer and more effective antimicrobial drugs by combating microorganisms that are resistant to multiple types of drugs.