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Background/Aim: Skin regeneration is the intrinsic ability to repair damaged skin tissues to regaining skin well-being. Processes of wound healing, a major part of skin regeneration, involve various types of cells, including keratinocytes and dermal fibroblasts, through their autocrine/paracrine signals. The releasable factors from keratinocytes were reported to influence dermal fibroblasts behavior during wound-healing processes. Here, we developed a strategy to modulate cytokine components and improve the secretome quality of HaCaT cells, a nontumorigenic immortalized keratinocyte cell line, via the treatment of cordycepin, and designated as cordycepin-induced HaCaT secretome (CHS). Materials and Methods: The bioactivities of CHS were investigated in vitro on human dermal fibroblasts (HDF). The effects of CHS on HDF proliferation, reactive oxygen species-scavenging, cell migration, extracellular matrix production and autophagy activation were investigated by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide cell viability assay, dichloro-dihydro-fluorescein diacetate, the wound-healing assay, reverse transcription polymerase chain reaction and immunofluorescent microscopy. Finally, Proteome Profiler™ Array was used to determine the composition of the secretome. Results: CHS induced fibroblast proliferation/migration, reactive oxygen species-scavenging property, regulation of extracellular matrix synthesis, and autophagy activation. Such enhanced bioactivities of CHS were related to the increase of some key cytokines, including C-X-C motif chemokine ligand 1, interleukin 1 receptor A, interleukin 8, macrophage migration-inhibitory factor, and serpin family E member 1. Conclusion: These findings highlight the implications of cordycepin alteration of the cytokine profile of the HaCaT secretome, which represents a novel biosubstance for the development of wound healing and skin regeneration products.