Nicotine is an addictive substance in cigarettes that causes dependence, making it difficult for smokers to quit. Treatment for nicotine dependence has limitations in terms of low effectiveness and side effects. Alternative treatments based on natural ingredients, such as coffee fruit skin or cascara (CA), which is rich in polyphenols, flavonoids, caffeine, and chlorogenic acid, offer neuroprotective potential to reduce nicotine dependence with minimal side effects. Fermentation using kombucha (KO) can increase the content of these bioactive compounds. This study aims to evaluate the effect of cascara fermented with kombucha on mice experiencing nicotine dependence. The study used a Conditioned Place Preference (CPP) design in male Swiss Webster mice induced by nicotine at a dose of 0.5 mg/kg BW. The test animals were given cascara and cascara-kombucha preparations at the same dose of 0.65 mL/20 g BW orally. In the pre-test stage, the initial residence time of the mice in each compartment was measured for baseline preference. The conditioning phase was conducted by administering test preparations and nicotine to selected compartments. The post-test measured the residence time in the nicotine compartment for 15 minutes. The CPP score was calculated as the difference between the post-test and pre-test residence times. Cascara and cascara-kombucha produced lower CPP scores than the nicotine group. Cascara-kombucha showed a better effect with a lower CPP score than cascara alone. Fermented cascara kombucha has suggested potential as an alternative therapy to overcome nicotine dependence.