An earlier trial of a school-based, preventative intervention, HealthWise South Africa, demonstrated some efficacy in preventing adolescent drinking and smoking in the Western Cape, South Africa. This was followed by the current implementation trial, which examined how implementation support conditions influenced adolescent drinking and smoking behavior change in the HealthWise intervention. The hybridized implementation-effectiveness trial included 34 schools (n = 2175 students) that provided student data at four waves through Grades 8 to 10. Implementation support conditions included a combination of two components (enhanced school environment and teacher consultation), resulting in four conditions: enhanced school environment, teacher consultation, both components, and standard delivery. Using configural frequency analysis, we examined how drinking and smoking behavior change differed across four configurations of intervention support longitudinally and by gender. For baseline non-smokers, results indicated sustained differences in abstention from smoking and smoking initiation between schools that received both support components and schools in the standard delivery condition. These results were primarily driven by girls. For baseline drinkers and smokers in the both components condition, changes in drinking were delayed until Grade 9 and smoking decayed by Grade 10. Results suggest that providing both school and teacher implementation support synergistically facilitates improved intervention outcomes both immediately following intervention and 2years later across schools with diverse resource levels. Future iterations of HealthWise, and other interventions, may benefit from a multilevel implementation support strategy to improve student outcomes. More research is needed to understand how to improve HealthWise effectiveness among boys.