The MECHANISMS study investigates how social norms for adolescent smoking and vaping are transmitted through school friendship networks, and is the first study to use behavioral economics methodology to assess smoking-related social norms. Here, we investigate the effects of selection homophily (the tendency to form friendships with similar peers) and peer influence (a social process whereby an individual’s behavior or attitudes are affected by peers acting as reference points for the individual) on experimentally measured smoking and vaping norms, and other smoking outcomes, in adolescents from high and middle-income settings. Full school year groups in six secondary schools in Northern Ireland (United Kingdom) and six secondary schools in Bogotá (Colombia) participated (n = 1344/1444, participation = 93.1%, target age 12–13 years). Over one semester, pupils received one previously tested school-based smoking prevention program (ASSIST or Dead Cool). Outcomes included experimentally measured smoking/vaping norms, self-report and objectively measured smoking behavior, and self-report smoking norms, intentions, susceptibility, attitudes, and psycho-social antecedents. We investigated selection homophily and peer influence using regressions and SIENA modeling. Regression results demonstrate lagged and contemporaneous selection homophily (odds ratios [ORs] = 0.87–1.26, p ≤ 0.01), and peer influence effects for various outcomes from average responses of friends, school classes, or school year groups (standardized coefficients [βs] = 0.07–0.55, ORs = 1.14–1.31, p ≤ 0.01). SIENA models showed that comparable proportions of smoking/vaping-based similarity between friends were due to selection homophily (32.8%) and peer influence (39.2%). A higher percentage of similarity between friends was due to selection homophily and/or peer influence for ASSIST schools compared to Dead Cool. Selection homophily was also more important in Bogotá, whilst peer influence was stronger in Northern Ireland. These findings support using social norms strategies in adolescent smoking prevention interventions. Future research should consider selection homophily and social influence jointly, and examine whether these findings translate to other high and low-middle-income settings with varying cultures and norms.