Antibiotic resistance is one of the critical issues, describing a significant social health complication globally. Hence, the discovery of novel antibiotics has acquired an increased attention particularly against drug-resistant pathogens. Natural products have served as potent therapeutics against pathogenic bacteria since the glorious age of antibiotics of the mid 20th century. This review outlines the various mechanistic candidates for dealing with multi-drug resistant pathogens and explores the terrestrial phytochemicals isolated from plants, lichens, insects, animals, fungi, bacteria, mushrooms, and minerals with reported antimicrobial activity, either alone or in combination with conventional antibiotics. Moreover, newly established tools are presented, including prebiotics, probiotics, synbiotics, bacteriophages, nanoparticles, and bacteriocins, supporting the progress of effective antibiotics to address the emergence of antibiotic-resistant infectious bacteria. Therefore, the current article may uncover promising drug candidates that can be used in drug discovery in the future.