The main reasons for the discontinuation of contact lens wear are ocular dryness and discomfort. Proteoglycan 4 (PRG4), a mucinous glycoprotein, and hyaluronic acid (HA), a nonsulfated linear glycosaminoglycan, are naturally present in the eye and contribute to ocular hydration and lubrication. This study aimed to investigate the impact of the structure of the recombinant human PRG4 (rhPRG4)/HA complex on contact lens properties, when one agent is grafted and the counterpart is physisorbed on the surface of model conventional or silicone contact lens materials. Investigation of the wettability, water retention, antifouling, and boundary lubricant properties of the prepared hydrogels showed that the rhPRG4/HA interactions varied with the rhPRG/HA configuration on the hydrogel surface as well as the composition of the underlying substrate used. The rhPRG4-physisorbed/HA-grafted sample was characterized by better antifouling and boundary lubricant properties on the model conventional hydrogels, while the HA-physisorbed/rhPRG4-grafted sample exhibited improved surface wettability, antifouling, and water-retentive properties on the model silicone hydrogels. The results of this study contribute to the design of biomimetic contact lens surfaces that work synergistically with ocular fluid-phase biological agents to enhance compatibility between the contact lens and the ocular environment, alleviating dry eye symptoms and improving comfort.