This cross-sectional study was designed to investigate the prevalence, knowledge, attitude, and predictors of waterpipe (WP) smoking among intermediate and secondary school adolescents in the Kingdom of Saudi Arabia (KSA). A self-administered anonymous questionnaire was used to collect data on demography, WP smoking status and patterns, the Arabic version of the Global Youth Tobacco Survey tool, and instruments to assess knowledge and attitude towards WP smoking. The Patient Health Questionnaire (PHQ-9) was also used. Descriptive and inferential statistical techniques were used. Modeling of WP smoking behavior was conducted using logistic regression. A total of 639 male students participated in this study. The prevalence of current WP and cigarette smokers were 17.7% and 14.6%, respectively. Out of the total population, 47.8% of students have the misconception that WP smoking is less harmful than cigarettes. A significant association (P < 0.05) of some demographic factors (age, school stage, residence, and parents' educational level) on WP smoking status was observed. Pleasure, socializing, and happiness represented the primary motives for initiating WP smoking. The majority of students had misconceptions about WP's health effects. More than 50% believed that smoking WP could ease anxiety, cause less harm, and has less addictive properties compared to cigarettes. Modeling suggested that the most significant predictors of WP smoking were cigarette smoking, depression, and the attitude index. Current findings warrant further research and official health programs to promote educational initiatives regarding WP smoking.