Background. Waterpipe nicotine dependence and its association with depressive symptoms and dual usage among adolescents are currently not examined in the literature. Adolescents are a vulnerable population that is susceptible to depression and initiation of tobacco use. We aim, in this novel study, to assess the association between depressive symptoms and waterpipe nicotine dependence among adolescents in Jordan, evaluate the association between waterpipe smoking status (waterpipe smoker vs. dual user) and waterpipe nicotine dependence, and assess the internal validity of the Waterpipe Nicotine Dependence Scale (WNDS). Method. A cross-sectional study among adolescents of grade 9th to 12th in Jordan was conducted through multistage cluster random sampling. The self-reported Arabic Youth Tobacco Use Composite Measure Questionnaire (YTUCM) was used to collect the surveys that include demographic information, smoking status, and the WNDS to assess waterpipe nicotine dependence and depressive symptoms. Multiple linear regression and the t-test were used to analyze the data. Findings. One thousand three hundred and three surveys were collected, of which 1082 were included in the study (443 males and 639 females). 64.9% of the sample were nontobacco users, while 20.1% were waterpipe- (WTP-) only smokers, 11.4% were dual users, and 3.7% were cigarettes-only users. After adjusting for weights, 66.6% were nonsmokers, 19.2% were WTP-only smokers, 10.2% were dual users, and 3.9% were cigarettes-only smokers. Using multiple linear regression, depressive symptoms were significantly associated with WTP nicotine dependence (β 0.618), upon adjusting for confounders. Furthermore, dual users were associated with higher WTP nicotine dependence (β 12.034) compared to WTP-only smokers after adjusting for confounders. Cronbach’s alpha for the WNDS was 0.955. Conclusions. Our study shows that there is a statistically significant association between depressive symptoms and WTP nicotine dependence and higher dependence among dual users compared to WTP-only smokers. The WNDS can be a useful tool to assess WTP nicotine dependence with high internal consistency. However, a longitudinal study is needed to further understand the association and temporality between the depressive symptoms and WTP nicotine dependence. Additionally, research is needed to shorten the WNDS while maintaining high internal consistency and assess the external validity of the WNDS and the short- and long-term consequences of dual usage.