Waterpipe smoking (WPS) is one of the most emerging popular trends in Lebanon, with a prevalence of 36.9%, the highest among all Middle Eastern countries. Thus, the primary objective of the study was to examine the factors associated with knowledge, attitudes, and practice (KAP) related to WPS among a representative sample of waterpipe smokers. The secondary objective was to examine the effect of KAP on cumulative waterpipe dose and dependence. This cross-sectional study was carried out between May and December 2018 and enrolled a representative sample of 1550 waterpipe smokers from all Lebanese districts. The questionnaire used was specifically designed for this study. High knowledge score (Beta = 0.02, p = 0.002) were significantly associated with higher waterpipe harm perception score. In addition, high knowledge score (Beta = 0.32, p = 0.007) were significantly associated with higher attitude score toward smoking ban. Higher waterpipe harm perception score (Beta = - 1.30, p < 0.001), higher attitude (Beta = - 0.21, p < 0.001), and higher knowledge score (Beta = - 0.11, p < 0.001) were significantly associated with lower waterpipe dependence. In addition, higher waterpipe dependence (Beta = 2.02, p < 0.001) was significantly associated with higher cumulative waterpipe smoking, while higher waterpipe harm perception score (Beta = - 1.96, p = 0.009) and higher knowledge score (Beta = 0.27, p < 0.001) were significantly associated with lower cumulative waterpipe smoking. Our main finding was that better knowledge and perception of the harmful effects of waterpipe were related to a better attitude toward smoking bans and a lower waterpipe smoking. Therefore, health care providers and policymakers should join efforts to make awareness campaigns across Lebanon and develop adequate interventions to curb the use of waterpipe among the population.