E-cigarettes have gained enormous popularity, and their use has increased drastically worldwide. However, little is known regarding adolescents' and adults' knowledge, attitudes, and practices in Saudi Arabia. We conducted a cross-sectional study using a self-administered online-modified WHO GATS questionnaire on a convenience sample approach. Data were collected between January and March 2021 after the alleviation of COVID-19 lockdown measures in Saudi Arabia. Univariate and multivariate regression models were developed to identify independent factors associated with knowledge, attitude, and practice. Our sample (1335) had a mean age of 26.45 ± 10.5 years; nearly half of the participants had poor knowledge about e-cigarettes. The usage and positive attitude were reported by 18.6% and 19.4%, respectively. Around 43.5% of e-cigarette users reported starting or increased use during the COVID-19 pandemic, while 9.5% of participants would recommend it to others. Logistic regressions showed that older participants were more likely to have poor knowledge (OR = 1.02, 95% C.I. = 1.01-1.03) and positive attitudes (OR = 0.98, 95% C.I. = 0.91-0.96). Male participants and smokers (OR = 3.0, 95% C.I. = 2.3-3.8) were more likely to have a positive attitude. However, younger participants were less likely to go for e-cigarettes (OR = 0.95, 95% C.I. = 0.93-0.97), while males (OR = 2.53, 95% C.I. = 1.65-3.86) and smokers (OR = 4.63, 95% C.I. = 3.47-6.18) were more likely to use them. This study indicated a high level of poor knowledge about e-cigarettes. A considerable proportion of participants reported usage and a positive attitude towards them. Older age, male gender, and being a smoker were the main elicited predictors for e-cigarette use.