Carbon dioxide (CO2) becomes supercritical above its critical pressure and temperature (Pc = 73.8 bar and Tc = 31.1 °C). Supercritical CO2 provides lubrication and additionally is able to fully dissolve the minimum quantity lubrication (MQL) added to its stream. Sc-CO2 coolant as a novel “sub-zero” cooling method is considered a green cooling and lubrication technology. It could offer advantages in the machining performance such as increased material removal rate (MRR) and tool life, and improved surface integrity. Therefore, in the present study, the effects of supercritical CO2 cooling (Sc-CO2) on the high-speed milling of titanium grade 5 (Ti6Al4V) using a CNC 5 axis milling machine equipped with a Sc-CO2 + MQL delivery system at various cutting parameters is investigated and compared with flood coolant milling using emulsion. Ti6Al4V is considered a difficult-to-cut material with a wide range of applications in the medical, energy, and aviation industries. No scientific report was found on the high-speed side milling of Ti6Al4V with end mills comparing Sc-CO2 + MQL with flood coolant milling. The effects of cutting parameters on tool wear, achievable MRR, surface integrity, and chip morphology were evaluated. Experimental results showed that the Sc-CO2 milling led to increased tool life, significantly lower cutting forces (up to 50 %), an increased surface microhardness (up to 30 %), and reduced surface roughness (up to 50 %), compared to flood coolant milling. Moreover, using Sc-CO2 + MQL coolant also reduced the machined surface contamination with oil and enhanced the chance of brittle-chip formation, causing a reduction in chips width and burrs height. This investigation revealed that the use of Sc-CO2 + MQL “sub-zero” cooling and lubrication method tends to have positive environmental impacts and improve productivity, machinability, and cleanliness aspects.