Polydimethylsiloxane (PDMS) is extensively used in the field of biomaterials. However, its hydrophobicity still limits its range of applications and makes it prone to biofouling. Various techniques are currently utilized to overcome this limitation, but most of them reduce some of the PDMS prime characteristics, such as its mechanical strength and optical transparency. In this work, we employed an original two-step coating process to bypass harsh treatments on PDMS like UV–ozone or plasma treatment. A pre-coating step of tannic acid-Fe­(III) complex was performed prior to the zwitterionization of the PDMS with poly­(glycidyl methacrylate-co-sulfobetaine methacrylate) or poly­(GMA-co-SBMA) by a “grafting-to” approach. Successful coating was evidenced by a decrease of the water-contact angle from 118° to 79°. The process was optimized, and the optimized coating condition led to a significant improvement of the PDMS biocompatibility while maintaining its mechanical property and optical transparency. In addition, a 90% reduction of Escherichia coli attachment and fibrinogen plasma protein, an 80% reduction of red blood cells and cells from whole-blood attachment, and a 60% reduction of platelets adhesion were measured. We further tested the potential of the zwitterionic PDMS material as a storage vessel for platelet-rich plasma under physiological conditions. Platelet activation was decreased from 10.95% using virgin PDMS to 3.35% with the coated sample in a period of 2 days.