E-cigarettes are the most commonly used tobacco product among youth. In addition to harm potential, e-cigarette use is associated with initiating cigarette smoking. Limited research exists whether susceptibility to e-cigarette use is a risk factor for future tobacco and other substance use initiation. This study examined associations between baseline e-cigarette susceptibility and initiation and past 30-day use of e-cigarettes and cigarettes as well as initiation of marijuana and alcohol one year later, after adjusting for other risk factors and sociodemographic confounders. The study sample consisted of 5156 nationally representative youth (12–17 years) who completed both waves 1 (2013–2014) and 2 (2014–2015) of the Population Assessment of Tobacco and Health (PATH) study and were never users of tobacco, marijuana, and alcohol in Wave 1. Youth who were susceptible to e-cigarettes had increased odds of initiating e-cigarettes (adjusted OR: 2.22, 95% CI: 1.55–3.18), marijuana (aOR: 1.66, 95% CI: 1.12–2.46), and alcohol (aOR: 1.61, 95% CI: 1.26–2.06) between waves, as well as past reporting 30-day e-cigarette use (aOR: 3.64, 95% CI: 1.93–6.89) in Wave 2. Additionally, cigarette susceptibility, but not e-cigarette susceptibility, was associated with cigarette initiation (aOR: 3.36, 95% CI: 1.95–5.82) and past 30-day use (aOR: 2.83, 95% CI: 1.34–5.97). Prevention policies, as well as future research, could target youth susceptible to e-cigarettes to reduce the current trends on the use of these alternative tobacco products. Such efforts may also reduce the use of cigarettes and other substances.