Objective. The purpose of this study was to reveal the effect of N-acetylcysteine (NAC) on random-skin flaps in rats. Introduction. N-acetylcysteine is an agent among free radical scavengers which is used primarily as a mucolitic agent. Experimental studies have demonstrated protective effects of NAC on hepatic, renal, lung, and intestinal injuries. Methods. Wistar female rats were divided into 2 groups (control and NAC group), and the NAC group received intramuscular injections for 7 days. Flaps were raised on day 2 and rats were sacrified on day 7. Skin samples from the second cm and fifth cm of the skin flap were collected for biochemical and histopathological examinations. Results. The mean necrotic area ratios in the control and NAC group were 38% and 12%, respectively (P < 0.001). Malondialdehyde (MDA) levels were significantly lower in skin samples collected from the control group as compared to samples obtained from the NAC group (P = 0.002). Superoxide dismustase (SOD) activity was significantly higher in the NAC group (P < 0.0001). Histopathologically, a significant increase in macrophage and fibroblast activity was observed in the NAC group. Mononuclear cell infiltration and fibroblast activity had increased, especially in samples from the fifth cm of the skin flap in the NAC group. The histopathological evaluation in the NAC group revealed protective effects of NAC. Conclusions. Treatment of rats with NAC significantly reduced flap necrosis and MDA levels while increasing SOD levels. These data suggest that NAC has a protective role in flap survival and demonstrates preventive effects against flap necrosis.