Abstract: In this paper, 343 nm femtosecond laser and as a comparison, 1030 nm femtosecond and 1064 nm nanosecond lasers were used for improving water vapor permeability (WVP) of polyurethane (PU) synthetic leather. The morphologies of micro-hole were comparatively studied via a scanning electron microscope (SEM) and a 3D laser scanning microscope. The results indicated that 343 nm femtosecond laser was optimal to obtain excellent and small drilled micro through-holes. Moreover, analysis of interaction mechanism between laser beam and PU film revealed that the micro-drilling by 343 nm femtosecond laser exhibited photochemical ablation only, micro-drilling by 1030 nm femtosecond laser caused both photochemical and photothermal ablation, while micro-holes drilled by 1064 nm nanosecond laser resulted in photothermal ablation. By measuring the WVP and tensile resistance of the laser-drilled leather, it was concluded that the higher micro-hole density, the higher WVP value and lower tensile resistance, and the increase of pulse overlap led to an increase of WVP and a decrease of tensile resistance. The diameter of micro-hole decreased from 45 μm to 30 μm and taper of micro-hole increased from 0.7° to 12.1° with pulse overlap decreased from 91.7% to 50%. And, the highest WVP growth ratio was 306% at 2550 per sq. cm and the pulse overlap was 91.7%.