Background The prevalence of e-cigarette use among adolescents is on the rise worldwide and in the Arab region as well. Youth are amongst the different age groups who are mostly affected by this practice. Objective The purpose of this study was to assess the knowledge and attitudes of Jordanian adolescent students toward e-cigarettes. Methods A cross-sectional study was conducted using a convenience sample of 500 male school students. A self-reported questionnaire was distributed to the students electronically through social media platforms. T-test was used to identify differences in adolescents’ knowledge and attitudes based on their use and non-use of e-cigarettes. Result and Discussion The results revealed that 35% of participants reported trying e-cigarettes and 43% reported trying tobacco cigarettes. The vast majority (97.2%) of the participants heard about e-cigarette, while 63% were not aware of its components. The majority of participants agreed that e-cigarette is dangerous (89.2%), is cleaner than tobacco smoking (55.6%), and that use of e-cigarettes can help to quit tobacco smoking (61.4%). Furthermore, the students who used tobacco and e-cigarettes had a significantly higher mean score of knowledge (p< .001) and a lower mean score of attitudes toward e-cigarettes (p< .001) than those who do not. Conclusion There is still a need to increase accurate knowledge about e-cigarettes among youth with special emphasis on adolescents. Health awareness campaigns about e-cigarettes including their composition and side effects are highly recommended.