We evaluated the performance of five different commercially available nanoparticle classes as additives for an oil-based lubrication system. While the silicon dioxide particles Aerosil® 300, RY300, and R972V tended to increase wear and friction in our 100Cr6 versus cast iron disc–disc contact, Aeroxide® P 25 and especially T 805 TiO2 nanoparticles showed superior anti-wear and anti-friction properties. The underlying tribological mechanism was investigated with optical microscopy, helium ion microscopy, and X-ray photoelectron spectroscopy. Subsequently, we formulated a stable lubrication system based on the best performing T 805 particles. Here, the base oil is a highly purified paraffin oil which was supplemented with 1 wt% T 805 TiO2 particles, 1 wt% Estisol® 242 or 1 wt% oleic acid, 0.15 wt% oleylamine, and 0.15 wt% Pluronic® RPE 2520. Superior lubrication and anti-wear properties of this formulation were demonstrated in 4-h test runs with a normal force of F N = 2.5 kN and a sliding velocity of 0.15 m/s in our disc–disc contact. Wear was significantly reduced along with a nearly 12-fold reduction in the friction coefficient, compared to the base oil (μftobase=0.155vs.μftoT805≈0.01). Using 100Cr6 disc–ball contacts, we additionally analyzed the properties of our lubrication system in the border friction regime under higher loads (F N = 0.5 kN) in 2-h runs. In particular, on the discs with lower engagement ratio, chemo-tribological protective layers were built, which protected the parts very well against wear.