Natural product like honey is well known for its compositional diversity, medicinal properties including anti-inflammatory role, wound repair efficacy and nutritional competence. This multi-dimensional character of honey attracts regenerative medicine researchers. However, flow behavior of honey restricts its applications as a sustainable biomaterial matrix. In this juncture this study develops honey-biomaterial formulations and fabricates fibrous scaffold through wet spinning technique towards regenerative medicine applications. The cell culture study demonstrates the bio-compatibility of the fabricated constructs for fibroblasts (3T3) and keratinocyte (HaCaT) through MTT assay and by scanning electron microscopy regarding adhesion and penetration of cells on the scaffold. Better performance has been exhibited by the honey-biomaterial based scaffolds in comparison to alginate fibrous construct. This study also shows better expression of prime molecules like collagen I and III in 3T3 and p63 and E-cadherin in HaCaT on honey based matrix than that of alginate matrix or control group. Thus present work develops a honey-based fibrous matrix with biocompatible interface for plausible tissue engineering applications. © 2011 IEEE.