Mentoring programs, which pair youth with caring, non-parental adults with the goal of promoting positive youth development, are an increasingly popular strategy for early intervention with at-risk youth. However, important questions remain about the extent to which these interventions improve youth outcomes. The present study involved a comprehensive meta-analysis of all outcome studies of intergenerational, one-on-one youth mentoring programs written in the English language between 1975 and 2017, using rigorous inclusion criteria designed to align with developmental theories of youth mentoring. Analysis of 70 mentoring outcome studies, with a sample size of 25,286 youth (average age of 12 years old), yielded a statistically significant effect of mentoring programs across all youth outcomes. The observed effect size fell within the medium/moderate range according to empirical guidelines derived from universal prevention programs for youth, and was consistent with past meta-analyses of youth mentoring. Moderation analyses indicated that programs serving a larger proportion of male youth, deploying a greater percentage of male mentors or mentors with a helping profession background, and requiring shorter meetings yielded larger effect sizes, as did evaluations that relied on questionnaires and youth self-report. Taken together, these findings provide some support for the efficacy of mentoring interventions, while also emphasizing the need to remain realistic about the modest impact of these programs as currently implemented, and highlighting opportunities for improving the quality and rigor of mentoring practices.