Microfluidics has been developing for two decades, and most of the microfluidic applications were developed on flat microfluidic platforms. In this study, we used a 3-axis micromilling machine, which was commonly used in many laboratories and factories, to manufacture adjustable microlens on three-dimensional substrates. From the experiments, it is clear that several factors were critical to the quality of the micro features on the three-dimensional substrate, including the plan of the cutting path, the profile of the cutting tool, and the depth of cut. After carefully planning the cutting path with UG software and accumulating experience, we could successfully manufacture precise micro features on a three-dimensional polymeric substrate, which could be bonded with another piece of polymeric substrate by solvent bonding or used as a mold insert to fabricate micro features on the PDMS substrates by PDMS casting technique. To clearly demonstrate this fabrication process, we designed and fabricated an PDMS-based adjustable microlens on semi-sphere PMMA substrate and red food dye was used to show there had no leakage after bonding.