The fuels (diesel/biodiesel blends) for diesel engines must possess a minimum of lubricating characteristics to prolong the life of some of the engine vital parts lubricated by the fuel itself. Hence, the tribological characteristic of the modified nanofluid fuel blends needs to be investigated for its suitability and sustainability. In the present study, an experimental analysis on the tribological aspect of fuel blends comprising 40% Acacia concinna biodiesel and 60% diesel (by volume) mixed with titanium dioxide (TiO2) nanoparticles in a concentration of 50–200 mg/l was conducted. The prepared fuel blends in varying volume concentrations were tested on a four-ball tribotester. The effects of varying operating parameters such as load and temperature as well as oxidation of biodiesel fuel blend on friction and wear behavior were evaluated with the help of three-dimensional (3D) surface plots (response surface methodology approach). Further, wear patch diameter, wear debris, wear volume, and flash temperature parameter were analyzed using optical micrographs and ferrographs. The obtained results revealed that despite having an influence of all parameters, the effect of TiO2 nanoparticles is more significant in improving the antiwear/friction characteristics of modified nanofluid fuel blends. It was observed that a TiO2 concentration of 150 mg/l in fuel blend was found to be the most suitable to reduce the friction, wear, and wear volume compared with those of diesel and biodiesel blend.