Non-medical use of prescription drugs (NMUPD) has become a threat to public health. In the United States, NMUPD is especially common in young adults (aged 18-25). Self-esteem is a robust psychosocial factor of substance use. The substance use literature also documents that self-esteem is associated with alcohol use through other cognitive factors, such as coping. Given the important role of coping in substance use intervention, it is important to understand how coping alters mechanisms underlying the effects of self-esteem on NMUPD. However, little research has explored mediational mechanisms among self-esteem, coping, and NMUPD. The current study sought to examine a hypothesized mediation model among self-esteem, coping, and NMUPD in college students. Data were collected online from 1052 undergraduates (aged 18 to 25; 723 females) in a large public university in Virginia. Participants reported their past-three-month NMUPD (i.e. opioids, sedatives, anxiolytics, and stimulants), self-esteem, and coping (13 domains; e.g. active coping and self-blame). Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to identify the factorial structure of coping. Structural equation modeling (SEM) was employed for examining the hypothesized mediation model. EFA and CFA identified a two-factor structure of coping (i.e. adaptive coping and maladaptive coping). SEM suggested that adaptive coping together with maladaptive coping completely mediated the relationship between self-esteem and NMUPD. The goodness-of-fit indicators suggest a good model fit (RMSEA = .04; CFI = .95; TLI = .93; WRMR = 1.11). Self-esteem appears to be a protective factor for NMUPD in college students, and its relationship with NMUPD is mediated by two types of coping. Future interventions targetting NMUPD among college students should attend to self-esteem and coping.