The success of skin tissue engineering for deep wound healing relies predominantly on the design of innovative and effective biomaterials. This study reports the synthesis and characterization of a new type of naturally-derived and macroporous interpenetrating polymer network (IPN) for skin repair. These biomaterials consist of a biologically active fibrous fibrin network polymerized within a mechanically robust and macroporous construct made of polyethylene glycol and biodegradable serum albumin (PEGDM-co-SAM). First, mesoporous PEGDM-co-SAM hydrogels were synthesized and subjected to cryotreatment to introduce an interconnected macroporous network. Subsequently, fibrin precursors were incorporated within the cryotreated PEG-based network and then allowed to spontaneously polymerize and form a sequential IPN. Rheological measurements indicated that fibrin-based sequential IPN hydrogels exhibited improved and tunable mechanical properties when compared to fibrin hydrogels alone. In vitro data showed that human dermal fibroblasts adhere, infiltrate and proliferate within the IPN constructs, and were able to secrete endogenous extracellular matrix proteins, namely collagen I and fibronectin. Furthermore, a preclinical study in mice demonstrated that IPNs were stable over 1-month following subcutaneous implantation, induced a minimal host inflammatory response, and displayed a substantial cellular infiltration and tissue remodeling within the constructs. Collectively, these data suggest that macroporous and mechanically reinforced fibrin-based sequential IPN hydrogels are promising three-dimensional platforms for dermal tissue regeneration.