Adolescent and young adult athletes disproportionately report misuse of prescription opioids (MPO) compared to their peers. Injury has been implicated as a possible risk factor for MPO among athletes, yet no study to date has addressed injury as it may relate to opioid misuse in athletes of all competition levels. For this dissertation, I explored injury as an associated factor with MPO among adolescent and young adult athletes. I further examined long-term influences of injury on incidence of MPO later in life as well as explore the relative role of additional risk factors for MPO among athletes with injury. To meet these study objectives, secondary data analysis of multiple waves of data from The National Longitudinal Study of Adolescent to Adult Health (Add Health) was completed. Problem Behavior Theory guided analysis of the relationship between injury, other protective and risk factors, and MPO. Bivariate and multivariable regression was used to identify risk factors for MPO in adolescence and young adulthood as well as initiation of MPO in middle adulthood. Classification tree analysis was used to assess predictive profiles for misuse of prescription opioids in adulthood. Injury significantly increased risk for MPO in adolescence and young adulthood among athletes when adjusting for relevant covariates. Injury did not significantly influence risk for initiation of MPO in middle adulthood. Use of other substances increased risk for MPO in adolescence and young adulthood as well as initiation of MPO in middle adulthood. Family history of substance abuse and having been diagnosed with depression significantly increased risk for initiation of MPO in middle adulthood. Predictive profiles for increased likelihood of MPO in middle adulthood included other prescription drug use, cocaine use, participant educational attainment of less than college, childhood physical abuse, and substance use prior to age 18. Substance use and mental health screening needs to be implemented in environments where injured athletes access healthcare to prevent MPO. Further research is needed to develop and evaluate targeted interventions for primary prevention of MPO in the population of adolescent and young adult athletes.