The aeronautical industry constantly strives for efficient technologies to facilitate hole-making in CFRP/Ti6Al4V structural components. The prime challenge in this direction is excessive tool wear because of the different engineering properties of both materials. Nanofluid minimum quantity lubrication (NF-MQL) is the latest technology to provide synergistic improvement in tool tribological properties and lubrication function during machining. In the current study, an MoS2-based NF-MQL system was applied during helical milling using a FIREX-coated tool. In-depth analysis of wear, a scanning electron microscope (SEM), and electron deposition spectroscopy (EDS) were used to evaluate workpiece elemental transfer and tool wear mechanisms. Experimental findings showed that 1% nanoparticles concentration in lubricant resulted in low tool wear of 13 µm after 10 holes. The SEM and EDS analyses depicted formation of tribo-film on the surface, resulting less severe wear and a reduced degree of adhesion. However, a low nanoparticle concentration of 0.5% resulted in 106 µm tool wear after 10 holes with slight evidence of tribo-film. Parametric analysis based on eccentricity, spindle speeds (individual for CFRP and Ti6Al4V), axial pitch, and tangential feed showed correlations with mechanical damage. An extended study of up to 200 holes showed diffusion of C element at a high rate as compared to metal elements such as W and Co. The lowest tool wear was observed using eccentricity level 1, spindle speed Ti6Al4V 1000 rpm, spindle speed CFRP 7500 rpm, tangential feed 0.01 mm/tooth, axial pitch 1.5 mm, and 1% of MoS2 nanoparticles.