The discovery of antibiotics was hailed as a historic breakthrough for the human race in the fight against bacterial and malignant infections. However, in a very short time, owing to their acute and aggressive nature, bacteria have developed resistance against antibiotics and other chemotherapeutics agents. Potentially, this situation could again result in bacterial infection outbreaks. Metal and metal oxide nanoparticles have been proven as better alternatives; the combination of antibiotics and metal oxide nanoparticles was shown to decrease the toxicity and enhance the antibacterial, antiviral, and anticancer efficacy of the agents. This review provides a detailed view about the role of metal and metal oxide nanoparticles in the treatment of infections in conjunction with antibiotics, their modes of action, and synergism. In addition, the problems of multidrug resistance are addressed and will allow the development of a comprehensive, reliable, and rational treatment plan. It is expected that this comprehensive review will lead to new research opportunities, which should be helpful for future applications in biomedical science.