Inexpensive and flexible CO2 laser rapid prototyping of polymer microfluidics is facing challenges due to the rough microchannel surface typically with a roughness Ra in the µm range produced directly through laser ablation. In this study, a wet chemical etching technique was developed and used successfully to carry out smoothing of microchannel surfaces fabricated on a polymethyl methacrylate substrate using CO2 laser direct writing. The microchannel surface roughness of a few µm was significantly reduced through etching in acetone diluted with ethanol in an ultrasonic bath in a short time cycle. The surface roughness Ra of below 10 nm could be achieved through etching in the heated etchant solution while without noted deformation in a microchannel structure. The mechanism to reduce surface roughness by the tunable solubility of a polymer in a liquid through concentration and temperature control is discussed with respect to the effect of the etching parameters: acetone concentration, etching time and the temperature of the etching solution. The results would be attractive for microfluidic chip applications when using laser prototyping.