In this article, we present a simple PDMS surface modification method based on poly(vinyl alcohol)/glycerol (PVA/Gly) solution immersion, self-assembled absorption, and heat treatment. The results of contact angle and ATR-FTIR demonstrate the superhydrophilic surface in modified PDMS. It can allow for the stable production of monodisperse droplet in a highly reproducible manner. In addition, we demonstrate the fabrication of monodisperse paclitaxel (PTX) loaded poly(l-lactic acid) (PLLA) microspheres on this kind of modification chip with solvent evaporation. The PLLA microspheres can be adjusted to a range of different sizes depending on the system flow rate. Determination of microsphere size is carried out by optical microscopy and image analysis to reveal less than 4% variation in microsphere size. Compared with the results of published papers, the presented data demonstrate that PTX-loaded PLLA microspheres show good physical properties (spherical and discrete), high-drug loading, encapsulation efficiency, a small initial burst, and sustained-release behavior due to outstanding monodispersity. With the characteristic to prepare high-quality, monodisperse, biodegradable microspheres, the versatile and simple microfluidic method facilitates the development of more reliable and reproducible drug delivery systems, which have great potential to benefit pharmaceutical and biological applications.