Suicide is the second leading cause of death for youths in the United States. More Latino adolescents report suicidal thoughts and/or behaviors (STBs) than youths of most other ethnic communities. Yet few studies have examined multiple psychosocial predictors of STBs in Latino youths using multiyear longitudinal designs. In this study, we evaluated the progression of STBs in 674 Mexican-origin youths (50% female) from fifth grade (10 years old) to 12th grade (17 years old) and identified psychosocial predictors of changes in STBs across this period. Latent growth curve models revealed that being female and later-generation status were associated with increasing prevalence in STBs across adolescence. Family conflict and peer conflict predicted increased STBs, whereas greater familism predicted less STBs. Thus, interpersonal relationships and cultural values contribute to the development of STBs in Mexican-origin youths and may be key levers for decreasing suicidality in this understudied but rapidly growing portion of the U.S. adolescent population.