Printed circuit boards (PCBs) are key components in computers, 5G, 6G, and other wireless communication devices. On the other hand, the manufacture of micro-holes in PCBs faces severe challenges. Conventional micro-drilling methods often encounter challenges such as poor surface quality and limited tool life. To overcome these issues, a novel micro-drilling method called cryogenic and ultrasonic-assisted micro-drilling (CUAMD) has been developed. This study compared four drilling methods to investigate the benefits of cryogenic and ultrasonic-assisted drilling in hybrid machining processes: conventional micro-drilling (CMD), cryogenic-assisted micro-drilling (CAMD), ultrasonic-assisted micro-drilling (UAMD), and cryogenic and ultrasonic-assisted micro-drilling (CUAMD). The experimental results unequivocally indicate that the utilization of cryogenic-assisted drilling leads to a significant reduction in cutting heat during the machining process. This not only contributes to an improvement in machining accuracy but also exerts a positive influence on tool life and surface morphology. Ultrasonic-assisted drilling separates chips into smaller volumes through high-frequency-vibration, effectively reducing the cutting forces. The high frequency of 38.25 kHz and high amplitude vibration of 5.16 μm of the ultrasonic spindle induced vibrations on the drill bit. Liquid nitrogen with a pressure and temperature of 28 kPa and − 196 °C, respectively, was used in the cryogenic-assisted method. The superior machining performance of the CUAMD approach was evaluated by comparing it to various methods, including cutting forces, tool flank wear, entrance/exit hole morphology, and chip formation. The CUAMD method avoids chip entanglement, suppresses burrs, and reduces the maximum cutting force, maximum torque, and exit hole damage factor Fd by 47.7 %, 56.1 %, and 42.5 %, respectively, compared with CMD.