The present study aimed to investigate the effect of nano-microcapsule-basic fibroblast growth factor (bFGF) combined with hypoxia-inducible factor-1 (HIF-1) on the random skin flap survival of rats. Male Sprague-Dawley rats were used to establish the McFarlane flap model and subsequently, all model rats were randomly divided into four groups: Control, bFGF, HIF-1 and bFGF combined with HIF-1. The model rats were treated with 2.5 µg/day bFGF and 1.0 µg/day HIF-1 for 5 days by intraperitoneal injection. On day 5 following treatment, the boundaries between necrotic and surviving regions were significantly inhibited by bFGF combined with HIF-1. bFGF combined with HIF-1 inhibited oxidative stresses and inflammatory factors in random skin flap survival of rats. bFGF combined with HIF-1 also activated the protein expression levels of cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF) in the random skin flap survival of rats. In conclusion, nano-microcapsule bFGF combined with HIF-1 prevented random skin flap survival in rats through antioxidative, anti-inflammatory and activation of the protein expression levels of COX-2 and VEGF.