Antimicrobial, antibiofilm adherent, fracture resistant nano zinc oxide (ZnO NP) formulations based on poly methyl methacrylate (PMMA) matrix were developed using a facile ex situ compression moulding technique. These formulations demonstrated potent, long-term biofilm-resisting effects against Candida albicans (9000 CFU to 1000 CFU) and Streptococcus mutans. Proposed mechanism of biofilm resistance was the release of metallic ions/metal oxide by 'particle-corrosion'. MTT and cellular proliferation assays confirmed both qualitatively and quantitatively equal human skin fibroblast cell line proliferations (approximately 75%) on both PMMA/ZnO formulation and neat PMMA. Mechanical performance was evaluated over a range of filler loading, and theoretical models derived from Einstein, Guth, Thomas and Quemade were chosen to predict the modulus of the nanoformulations. All the models gave better fitting at lower filler content, which could be due to restricted mobility of the polymer chains by the constrained zone/interfacial rigid amorphous zone and also due to stress absorption by the highly energized NPs. Fracture mechanics were clearly described based on substantial experimental evidence surrounding crack prevention in the initial zones of fracture. Filler-polymer interactions at the morphological and structural levels were elucidated through FTIR, XRD, SEM, TEM and AFM analyses. Major clinical challenges in cancer patient rehabilitation and routine denture therapy are frequent breakage of the prostheses and microbial colonization on the prostheses/tissues. In the present study, we succeeded in developing an antimicrobial, mechanically improved fracture resistant, biocompatible nanoformulation in a facile manner without the bio-toxic effects of surface modifiers/functionalization. This PMMA/ZnO nanoformulation could serve as a cost effective breakthrough biomaterial in the field of prosthetic rehabilitation and local drug delivery scaffolds for abused tissues.