Adolescents experiencing societal vulnerability are at heightened risk of smoking uptake, exacerbating health disparities. To address this, the KickAsh!-intervention was co-created with adolescents and youth workers in Flanders, Belgium, using the intervention mapping protocol (IMP), aiming to prevent smoking uptake among 10- to 16-year-olds, particularly those from disadvantaged backgrounds. This study evaluates its effectiveness on adolescents’ smoking initiation behaviour and related determinants: smoking intention, attitude, self-efficacy beliefs, coping planning, perceived subjective norms, perceived social pressure, risk perception, and perceived smoking behaviour of peers and youth workers. A nonrandomized cluster-controlled trial was conducted across 23 youth social work organizations, with 12 implementing the intervention over four months. Co-creation organizations were pre-assigned to the intervention group. Data were collected via questionnaires at baseline, post-intervention, and seven-month follow-up (total N = 670; mean age = 12.85years, SD = 2.40; 63.2% boys). Generalized linear mixed models (GLMMs) in R were used to analyse intervention effects. A significant intervention effect was found for coping planning at post-test (B = 0.57, SE = 0.28, P = .04) and follow-up (B = 1.32, SE = 0.29, P < .001), with intervention participants showing an increase in preparing strategies to resist smoking. No significant effects were observed for smoking initiation behaviour or other determinants. This study found that combining co-creation with the IMP to develop a smoking prevention intervention yielded limited effects. High antismoking baseline levels and irregular adolescent attendance may have limited impact, highlighting challenges for implementing and evaluating interventions in youth social work settings.