This investigation sought to characterize the combined influence of cutting-edge microgeometry and cooling/lubricating strategies on process thermo-mechanics and the resultant surface integrity in orthogonal machining of the Ti-6Al-4V alloy. Reverse waterfall cutting inserts were prepared with varying cutting-edge geometries, and machining experiments were conducted under cryogenic cooling with liquid nitrogen (LN2), minimum quantity lubrication (MQL), and dry machining conditions, using constant machining parameters. The induced surface integrity was characterized in terms of the developed cutting forces and through-thickness microhardness, grain morphology, dislocation generation, and residual stress formation. The experimental results revealed that the governing process physics are strongly influenced by variation in the implemented machining parameters. As a greater proportion of the cutting edge is distributed on the flank face, competing mechanical ploughing and thermal-based frictional effects both become more pronounced. Utilization of advanced cooling strategies to control cutting interface thermal gradients thus provides a processing route to generate tailored microstructures and surface integrity during the machining of this alloy.