In peritoneal dialysis (PD), the catheter, usually made of silicone, has been considered the “lifeline” of the patient. However, the PD catheter also serves as a nidus for bacterial infection. Furthermore, complications can result from fibrin deposition and omental wrapping of the catheter, which obstructs the dialysate flow. In this work, a crosslinked agarose (AG) polymer layer is covalently grafted as a microscale coating on the silicone surface. This coating reduces Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa biofilm formation by more than two orders of magnitude. In addition, cell and platelet adhesion and protein adsorption is also reduced by ≥90%. Without compromising the antibacterial and antifouling property, further improvement in hemocompatibility, as shown by the inhibition of platelet adhesion and activation, prolonged plasma recalcification time and lower hemolysis degree, is achieved by co-immobilization of 2.6 μg cm−2 of heparin (HEP) in the agarose coating. The AG–HEP coatings are not cytotoxic to mammalian cells, and are stable for extended periods in lysozyme aqueous solution and under autoclaving at 121 °C for 20 min.