The emergence of microorganisms resistant to antimicrobial therapies, associated with the decline in the development of new drugs, including antibiotics, antifungals, and antivirals, highlights the need for alternative strategies to combat microorganisms that cause infections, especially multidrug-resistant bacteria. Polymethylmethacrylate (PMMA) is a material widely used in the biomedical field, with uses ranging from surgical implants, bone cements, and dental devices, to laboratory equipment and three-dimensional models for surgical planning. Despite its multiple applications, PMMA has the disadvantage of favoring microbial adhesion, due to the porous nature of the material, associated with poor bond strength, thermal instability and water sorption in the oral environment, which can contribute to infection development. To mitigate this problem, the scientific community is looking to modify PMMA to give it antimicrobial properties. This review presents possible approaches that include changes to the topography of PMMA, creating textured or nanostructured surfaces, and chemical modifications, such as incorporating antimicrobial agents into the PMMA matrix or surface treatments. Both strategies aim to hinder the adhesion and growth of microorganisms. In addition, combining these approaches seeks a synergistic effect and could become a promising mechanism for preventing infections.