A multi-layered artificial skin, which is mainly consisted of three layers of silicone elastomer, printed paper, and resin plate, is expected as sealing material of facial defects. However, sweating phenomenon from the surface of missing parts results in insanitary conditions to the skin surface, and micro-drilled holes are required to improve the breathability of the multi-layered artificial skin as human’s sweat glands. High-efficiency processing is expected by using a high pulse repetition-rate laser. Although ultra-short pulsed laser is used, a continuous long time laser irradiation deteriorated the aesthetic quality of multi-layered artificial skin because of heat accumulation corresponding to the high pulse-repetition-rate. Therefore, laser irradiation method with the high-efficiency and good-aesthetic-quality was experimentally investigated by using picosecond pulsed laser of 1064 nm wavelength. The laser irradiation method, which can reduce the heat affected zone at the adhesion part between the print paper and the silicone elastomer, was effective in order to improve the esthetic quality of drilled hole for the multi-layered artificial skin. The discoloration area around drilled hole on multilayered artificial skin could be reduced by dividing method of laser shot number at the same irradiation point to provide non-irradiation time. A long non-irradiation time resulted in the reduction of discoloration area around drilled hole on multi-layered artificial skin under the similar heat input condition.