N-acetylcysteine (NAC), a glutamate-modulating agent with antioxidant and anti-inflammatory properties, has been considered as a potential anti-addictive drug. Beneficial effects were reported for cocaine, cannabis, and tobacco addicts, but the effect of NAC in alcoholics or in alcohol animal models is unknown. The aggravation of alcohol withdrawal symptoms, such as anxiety, has been associated with increased levels of serum corticosterone and leptin. Thus, the aim of this study was to assess the effects of NAC on anxiety, as well as corticosterone and leptin serum levels, after cessation of chronic alcohol treatment in rats. Male Wistar rats were treated with 2 g/kg ethanol, twice daily, by gavage for 30 days; control animals received an appropriate dose of glucose to balance caloric intake. Rats were treated for 4 days with NAC (60 and 90 mg/kg, intra-peritoneally [i.p.]) or saline after alcohol cessation. Twenty-four hours after the last treatment, rats were exposed to a 5-min session in the open-field test (OF). Corticosterone and leptin serum levels were determined by ELISA in samples collected within 30 min after the OF. Results showed that rats were hypoactive (decreased rearing, peripheral, and total crossings), and that corticosterone and leptin levels were increased 5 days after alcohol cessation. Four days of NAC prevented the behavioral and biochemical changes brought about by alcohol cessation. We suggest that, in addition to the anti-addictive properties reported for other drugs of abuse, NAC is potentially useful in the management of alcohol withdrawal.