Fuyuan Huoxue decoction (FHD) is a traditional Chinese medicine that can promote blood circulation, inhibit inflammatory reactions and effectively relieve pain. This study investigated the effect of FHD on rat skin flap survival and the p38 MAPK/ IKK/NF-kappa B pathway. Methods: The pathological condition of the flap tissue was examined by H&E staining. The expression levels of CD34 and VEGF in skin flap tissues were examined by immunohistochemistry. The levels of TNF-alpha, IL-6, CRP, and HO-1, superoxide dismutase (SOD) activity, and MDA content were detected by ELISA. The protein expression levels of Bax, Bcl-2, cleaved-caspase 3, p-IKK alpha beta, p-p38, p-p65, alpha-SMA, CK14, CK15, and SOX2 were detected by western blotting. Results: Fuyuan Huoxue decoction upregulated the levels of CD34, VEGF, and Bcl-2, downregulated the expression of TNF-beta, IL-6, p-IKK alpha beta, P-P38, P-P65, Bax, and cleaved-caspase 3, increased the activity of SOD, and inhibited the level of MDA. In addition, FHD promoted the proliferation and differentiation of skin flap. Conclusions: Fuyuan Huoxue decoction improved the survival of the rat skin flap model by regulating the p38MAPK/IKK/NF-kappa B signaling pathway, and the mechanism may be related to the promotion of skin flap proliferation, differentiation, and revascularization and the inhibition of inflammation and oxidative stress.