Nicotine-diet interactions have a particular importance on human health. Some food substances are subject to change hepatic CYP2A6 metabolism rate for nicotine and its levels in smokers consequently. This study investigates the effect of pomegranate and licorice drinks on nicotine metabolism, by a new developed and validated method for simultaneous determination of nicotine with its major metabolites (cotinine and nicotine N-oxide) in human urine, utilizing LC ESI-orbitrap-MS. Twenty-four Jordanian healthy and smoker volunteers were participated in two equal groups, crossover design for each of pomegranate and licorice test drink. In the study periods each group assigned either to drink test juice three times a day or to be avoided from test drink for 7 successive days, and then both groups switched their drink treatment in subsequent period. Early morning urine samples were collected from all volunteers after each period. Nicotine metabolism rate was evaluated from nicotine/cotinine and nicotine/nicotine N-oxide ratios in urine. A consistent trend of increase in metabolism rate for nicotine was observed from urine analysis under pomegranate or licorice drink conditions compared to control conditions. Pomegranate and licorice drinks are increasing the metabolism rate for nicotine in terms of induction effect for hepatic cytochrome p450 enzymes.