Biofouling has long been a problem for biomaterials, so being able to control the fouling on the surface of a biomaterial would be ideal. In this study a copolymer system was designed comprising three moieties: an epoxy containing group, glycidyl methacrylate (GMA); a thermoresponsive segment, N-isopropylacrylamide (NIPAAm); and an antifouling zwitterionic unit, sulfobetaine methacrylate (SBMA). The copolymers (pGSN), synthesized via free radical polymerization with these 3 moieties, were then grafted onto polydimethylsiloxane (PDMS). The presence of a critical temperature for both the copolymers and the coated PDMS was evidenced by particle size and contact angle measurements. The coated PDMS exhibited controllable temperature-dependent antifouling behaviors and stimuli-responsive phase characteristics in the presence of salts. The interactions of the coated PDMS with biomolecules were tested via attachment of fibrinogen protein, platelets, human whole blood, and tumor cells (HT1080). The attachment and detachment of these biomolecules were studied at different temperatures. Exposed hydrophobic domains of thermoresponsive NIPAAm-rich pGSN containing NIPAAm at 56 mol% generally allows molecular and cellular attachment on the PDMS surface at 37 °C. On the other hand, the coated PDMS with a relatively high content of SBMA (>41 mol%) in the copolymer started to exhibit fouling resistance and lower the thermoresponsive properties. Interestingly, the incorporation of zwitterionic SBMA units into the copolymers was found to accelerate the hydration of the PDMS surfaces and resulted in biomolecular and cellular detachment at 25 °C, which is comparable to the detachment at 4 °C. This modified surface behavior is found to be consistent through all biofouling tests.