Carbon fiber reinforced plastic (CFRP)/Ti6Al4V stacks are widely used in the aircraft industry, and drilling these stacks is essential during the assembly process. To solve the problem of high drilling temperatures in CFRP/Ti6Al4V stacks, which lead to poor tool life and hole quality, the effects of three cooling strategies compose minimum quantity lubrication (MQL), water-based coolant, and internal air cooling, were investigated in this study. Tensile/compressive strength and fatigue-life tests were conducted to evaluate the applicability of the cooling medium before drilling. Then, low-frequency vibration-assisted drilling of CFRP/Ti6Al4V stacks was performed to investigate and analyze their machinability under the three cooling strategies by analyzing the drilling temperature, thrust force, tool wear, chip removal capacity, and hole quality. The results show that the selected cooling media, including Rhenus XT46 and Accu-Lube LB2000, are applicable in CFRP drilling, whereas the adopted media, compared with water, have little influence on the tensile/compressive strength and fatigue life of the CFRP. Compared with internal air cooling and MQL, water-based coolant can more effectively improve the machinability of CFRP/Ti6Al4V stacks, decreasing the CFRP drilling temperature by 41.6 % and 40.1 %, respectively, while the reductions in the Ti6Al4V drilling temperature are 76.7 % and 57.4 %, respectively. Meanwhile, under water-based coolants, the thrust force reductions in the drilling of CFRP are 13.1 % and 11.7 %, whereas those in the drilling of Ti6Al4V are 11.0 % and 7.8 %, respectively, compared with the internal air and MQL. In addition, under the water-based coolant condition, the tool wear rate is the slowest and the hole quality is the best among the three cooling strategies, whereas a high injection pressure further decreases the VBmax value. Furthermore, under the water-based coolant conditions, the Ti6Al4V exit burr height and CFRP exit delamination are the lowest. These findings provide useful insights into improving the machinability of CFRP/Ti6Al4V stacks in the aerospace industry, particularly for drilling that requires high-quality holes and a long tool life.