The global adolescent population is larger than ever before and is rapidly urbanizing. Global surveillance systems to monitor youth health typically use household- and school-based recruitment methods. These systems risk not reaching the most marginalized youth made vulnerable by conditions of migration, civil conflict, and other forms of individual and structural vulnerability. We describe the methodology of the Well-Being of Adolescents in Vulnerable Environments survey, which used respondent-driven sampling (RDS) to recruit male and female youth aged 15–19 years and living in economically distressed urban settings in Baltimore, MD; Johannesburg, South Africa; Ibadan, Nigeria; New Delhi, India; and Shanghai, China (migrant youth only) for a cross-sectional study. We describe a shared recruitment and survey administration protocol across the five sites, present recruitment parameters, and illustrate challenges and necessary adaptations for use of RDS with youth in disadvantaged urban settings. We describe the reach of RDS into populations of youth who may be missed by traditional household- and school-based sampling. Across all sites, an estimated 9.6% were unstably housed; among those enrolled in school, absenteeism was pervasive with 29% having missed over 6 days of school in the past month. Overall findings confirm the feasibility, efficiency, and utility of RDS in quickly reaching diverse samples of youth, including those both in and out of school and those unstably housed, and provide direction for optimizing RDS methods with this population. In our rapidly urbanizing global landscape with an unprecedented youth population, RDS may serve as a valuable tool in complementing existing household- and school-based methods for health-related surveillance that can guide policy.