High-fidelity preclinical in vitro tissue models can reduce the failure rate of drugs entering clinical trials. Collagen and hyaluronic acid (HA) are major components of the extracellular matrix of many native tissues and affect therapeutic macromolecule diffusion and recovery through tissues. Although collagen and HA are commonly used in tissue engineering, the physical and mechanical properties of these materials are variable and depend highly on processing conditions. In this study, HA was chemically modified and crosslinked via hydrazone bonds to form interpenetrating networks of crosslinked HA (HAX) with collagen (Col). These networks enabled a wide range of mechanical properties, including stiffness and swellability, and microstructures, such as pore morphology and size, that can better recapitulate diverse tissues. We utilized these interpenetrating ColHAX hydrogels as in vitro tissue models to examine macromolecular transport and recovery for early-stage drug screening. Hydrogel formulations with varying collagen and HAX concentrations imparted different gel properties based on the ratio of collagen to HAX. These gels were stable and swelled up to 170% of their original mass, and the storage moduli of the ColHAX gels increased over an order of magnitude by increasing collagen and HA concentration. Interestingly, when HAX concentration was constant and collagen concentration increased, both the pore size and spatial colocalization of collagen and HA increased. HA in the system dominated the ζ-potentials of the gels. The hydrogel and macromolecule properties impacted the mass transport and recovery of lysozyme, β-lactoglobulin, and bovine serum albumin (BSA) from the ColHAX gels─large molecules were largely impacted by mesh size, whereas small molecules were influenced primarily by electrostatic forces. Overall, the tunable properties demonstrated by the ColHAX hydrogels can be used to mimic different tissues for early-stage assays to understand drug transport and its relationship to matrix properties.