Antimicrobial agents are potential additives in concrete mixes to combat biodeterioration. However, their impact on the compressive strength of high-performance concrete (HPC) remains limited. In this study, response surface methodology (RSM) was employed to develop 21 combinations of nano-sized TiO₂ and ZnO, ranging from 0-2% by weight of the cement in HPC. The 28-day compressive strength of the samples served as response factors to evaluate the effects of these combinations. The RSM modelling results revealed that ZnO reduced compressive strength as its content increased from 0-2%, while TiO₂ enhanced compressive strength by up to 17% in HPC with 2% TiO₂. Combined effects indicated that compressive strengths between 81-100 MPa could be achieved by optimizing TiO₂ content and varying ZnO content within the 0-2% range. The developed quadratic model, with a p-value of <0.0001, F-value of 23.4, and R² of 0.8863, accurately depicted the effects of the nanoparticles (NPs) on compressive strengths, with most residual values falling within ±3.