Overcoming the global concern of antibiotic resistance is one of the biggest challenges faced by scientists today, and the key to tackling this issue of emerging infectious diseases is the development of next-generation antimicrobials. The rapid emergence of multi-drug resistant microbes, superbugs and mutated strains of viruses has fuelled the search for new and alternative antimicrobial agents with broad-spectrum biocidal activity. Biomaterials, ranging from macroscopic polymers, proteins, and peptides to nanoscale materials such as nanoparticles, nanotubes and nanosheets have emerged as effective antimicrobials. An extensive body of research has established the antibacterial and antiviral efficiencies of different types of biomaterials. What make these materials unique are the different modes through which they interact and exert their antimicrobial activity. This review provides a comprehensive and detailed overview of the diverse modes of interaction between biomaterials and bacteria and viruses, and sheds light on how different biomaterials influence and modulate antimicrobial mechanisms to achieve a high degree of therapeutic efficacy without resistance generation.