Water-based fluids containing nanostructured fullerene and 18-crown ether-6 were investigated. The effects of those nanostructured additives on the tribological performance of titanium and its alloys as potential biomaterials were analyzed. Experimentally, tribology tests were conducted using a Ti–6Al–4V ball against a disk made of pure titanium as a simplified model of the material rubbing pair. Lubrication mechanisms were studied by comparing the nanostructures, viscosities, and frictions. Results showed that the fullerene in deionized water provided the lowest viscosity and friction. Crown ether, on the other hand, provided high friction and shear. Our analysis indicated that the fullerene was weakly interacted with water compared with the crown ether, resulting in an extended low friction in the boundary lubrication regime. The crown ether required extra energy in order to slide or roll. This led to a high friction. This finding opens the possibilities for lubrication design and optimization for biological and engineering applications in general.