The complicated behavior of modified asphalt binders in the asphalt matrix makes it difficult to predict their consistency, particularly when waste materials and two or more modifiers are present. This research investigated the effect of waste denim fiber (WDF) and/or nanosilica (NS) on the physical characteristics of asphalt modified by sludge tire pyrolysis oil (S-TPO). Response surface methodology (RSM) has also been investigated as a potential method to develop prediction models for the penetration, softening point, and temperature sensitivity of control and modified asphalt binders. According to the experimental work's findings, treated asphalt's consistency greatly improved up to a particular level of WDF and/or NS particle content. In comparison to S-TPO-modified asphalt, all modified asphalt binders with WDF and/or NS displayed reduced penetration and greater softening point and penetration index values. This finding may be the result of the interactions between the modifiers utilized, which improve stiffness and temperature resistance. However, there was a minor decrease in consistency at high concentrations of WDF and NS compared to that at lower concentrations, which might be caused by the particles aggregating at such high concentrations. In contrast to the individual modifiers, which have no significant impacts, the composite WDF/NS has a substantial impact on the consistency of S-TPO-modified asphalt, according to RSM analysis. For all responses, the developed RSM-based predictive models showed a correlation coefficient (R2) of greater than 0.74. This shows that the addition of WDF and/or NS was responsible for at least 74 of the changes in the consistency of S-TPO-modified asphalt. The multi-objective optimization revealed that the optimum contents for the S-TPO-modified asphalt to achieve the desired consistency were 5.1 WDF and 2.6 NS. Overall, it was discovered that RSM is an effective method for accurately predicting the consistency of S-TPO-modified asphalt with WDF and/or NS particles. © 2023 The Authors