Significance Cigarette smoking is the leading cause of preventable disease and death in the United States. Severe withdrawal symptoms are the reason most people have a hard time quitting smoking. AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and is activated in response to cellular stressors. We discovered that the AMPK pathway is activated following chronic nicotine use but is repressed following nicotine withdrawal. We reasoned that increasing pAMPK levels pharmacologically might reduce symptoms of nicotine withdrawal. After giving mice metformin, an AMPK activator, we were able to reduce nicotine withdrawal, and found that this was dependent on the presence of the AMPK protein in the hippocampus. This study suggests that AMPK activation could be a target for smoking cessation.