MXenes, a rapidly emerging class of two-dimensional transition metal carbides and nitrides, exhibit unique physicochemical properties that make them promising antibiofilm materials. This review provides a mechanistic perspective on MXene-mediated control of polymicrobial biofilms, focusing on membrane disruption, oxidative stress induction, quorum sensing interference, and inhibition of microbial co-adhesion. Recent advances in MXene-based coatings, composites, and multifunctional delivery platforms for wound care, implant-associated infections, aquaculture antifouling, drug delivery, and photothermal therapy are critically discussed, highlighting their potential in next-generation stimulus-responsive antibiofilm systems. The central novelty of this review lies in its dedicated focus on MXenes as inhibitors of polymicrobial biofilms, an area that previous reviews have not delved upon. As this area remains insufficiently explored, this work specifically examines the interactions of MXenes within bacterial–fungal consortia and their implications for biofilm persistence and pathogenic synergy. Furthermore, this review uniquely highlights two underexplored antibiofilm mechanisms of MXenes: disruption of microbial amyloid matrices and attenuation of quorum sensing pathways, both of which may be possible anti-infective measures in future. Importantly, challenges associated with MXene oxidation, limited shelf life, and environmental instability are addressed alongside emerging stabilization and surface-engineering strategies. Future perspectives emphasize the integration of multi-omics approaches and AI-driven predictive modeling to rationally tailor MXene surface chemistry for enhanced antibiofilm efficacy while minimizing cytotoxicity. Collectively, this review establishes a translational framework for the rational development of MXene-based platforms aimed at combating complex biofilm-associated infections.