Background: We examined e-cigarette use as a prospective predictor of alcohol and marijuana abuse symptoms in a sample consisting of Native Hawaiian and Other Pacific Islander (NHPI), Filipino, Asian (i.e., Japanese, Chinese, Korean), and White young adults. NHPI represent a highly vulnerable group with regard to substance use and are severely understudied. Methods: Data were collected from 1463 young adults (M age = 22.2, SD = 3.2; 59.5% women) enrolled across community colleges in Hawai‘i at two time-points six months apart. Results: Higher frequency of e-cigarette use at baseline was predictive of higher alcohol (B = 0.06, SE = 0.02, p < 0.01) and marijuana (B = 0.06, SE = 0.02, p < 0.01) use problems at six-month follow up, adjusting for baseline cigarette smoking, problem alcohol/marijuana use, sensation seeking, and demographic variables. Ethnicity was found to significantly moderate the relationship between baseline e-cigarette use and problem marijuana use later, such that White and NHPI ethnicities were particularly vulnerable to the effects of e-cigarette use on problem marijuana use. Conclusion: NHPI are often combined with Asians in national surveys, which obfuscates the higher risks faced by NHPI compared with groups that are routinely classified as Asians (e.g., Chinese, Japanese, Filipinos). The current research highlights the NHPI’s vulnerability in terms of the effects of e-cigarette use on marijuana and alcohol abuse symptoms.