Cold atmospheric plasma (CAP) is an emerging biomedical technology exemplified by its antimicrobial and anti-neoplastic applications. While acidic fibroblast growth factor (aFGF) has been a long-standing potent mitogen for cells from various origins. In this study, we conducted a direct comparison between CAP and aFGF and investigated their collaboration during wound healing, angiogenesis, neurogenesis, and osteogenesis. This work was systematically performed at the tissue, cellular, protein, and gene levels, using histochemical staining, flow cytometry, ELISA, and PCR, respectively. The results showed that the enhancement on would healing and angiogenesis by CAP and aFGF were synergistic. The former was manifested by increased murine fibroblast proliferation and reduced cutaneous tissue inflammation, whereas the latter by upregulated proangiogenic markers in vivo, e.g. CD31, VEGF and TGF-, and downregulated antiangiogenic proteins in vitro, e.g. angiostatin and angiopoietin-2, respectively. In addition, aFGF outperformed CAP during neurogenesis, which was evidenced by superior neurite outgrowth, while CAP exceeded aFGF in osteogenesis, which was demonstrated by more substantial bone nodule formation. These findings not only support the fact that both CAP and aFGF are potent multifunctional agents during tissue regeneration, but also highlight the potential of multimodal therapy combining the individual advantages of CAP and aFGF.