Polydimethylsiloxane (PDMS) elastomer has emerged as one of the most frequently applied materials in microfluidics. However, precise and large-scale surface micromachining of PDMS remains challenging, limiting applications of PDMS for microfluidic structures with high-resolution features. Herein, surface patterning of PDMS was achieved using a simple yet effective method combining direct photolithography followed by reactive-ion etching (RIE). This method incorporated a unique step of using oxygen plasma to activate PDMS surfaces to a hydrophilic state, thereby enabling improved adhesion of photoresist on top of PDMS surfaces for subsequent photolithography. RIE was applied to transfer patterns from photoresist to underlying PDMS thin films. Systematic experiments were conducted in the present work to characterize PDMS etch rate and etch selectivity of PDMS to photoresist as a function of various RIE parameters, including pressure, RF power, and gas flow rate and composition. We further compared two common RIE systems with and without bias power and employed inductively coupled plasma and capacitively coupled plasma sources, respectively, in terms of their PDMS etching performances. The RIE-based PDMS surface micromachining technique is compatible with conventional Si-based surface and bulk micromachining techniques, thus opening promising opportunities for generating hybrid microfluidic devices with novel functionalities.