To examine the associations between early onset of nonmedical prescription stimulant use (NPSU) and cocaine use. Nationally representative samples of high school seniors were surveyed annually. Data were collected via self-administered questionnaires in nationally representative public and private schools in the United States (1976-2020) as part of the Monitoring the Future Study. The sample consisted of 45 cohorts of 12th grade students (N = 121 909). The main outcome was lifetime, past-year, and past-month cocaine use. An estimated one in every 10 (10.1%) individuals reported lifetime NPSU while 8.5% reported any cocaine use. The vast majority of youth (87.2%) initiated NPSU before cocaine among those who reported both substances. Cocaine use was most prevalent among youth who reported early onset of NPSU in 8th grade or earlier (51.7%) followed by those who reported later onset of NPSU in 12th grade (24.7%), and those who never initiated NPSU (3.7%). Binary logistic regression analysis indicated that early onset of NPSU had greater adjusted odds of cocaine use compared to those with later onset of NPSU or those who never reported NPSU. Moreover, the adjusted odds of cocaine use were higher for adolescents who initiated NPSU before or after medical use of prescription stimulants compared to those with no history of medical use or NPSU. Similar results were found for lifetime, past-year, and past-month cocaine use as a function of NPSU onset; this association was stronger among more recent cohorts. Early onset of NPSU appears to be a signal of increased risk of cocaine use among US adolescents. NPSU should be included in screening and early prevention strategies among secondary school students. Health professionals, school officials, and families are encouraged to monitor youth for NPSU based on the increased risk of later cocaine use and related consequences.