Introduction: Vaccination is an effective and safe strategy to prevent Human papillomavirus (HPV) infection and related harms. Despite various efforts by French authorities to improve HPV vaccine coverage (VC) these past few years, VC has remained far lower than in most other high-income countries. To improve it, we have coconstructed with stakeholders a school-based and primary care-based multicomponent intervention, and plan to evaluate its effectiveness, efficiency and implementation through a cluster randomised controlled trial (cRCT). Methods and analysis: This pragmatic cRCT uses an incomplete factorial design to evaluate three components applied alone or in combination: (1) adolescents and parents' education and motivation at school, using eHealth tools and participatory learning; (2) general practitioners' training on HPV using motivational interviewing techniques and provision of a decision aid tool; (3) free-of-charge access to vaccination at school. Eligible municipalities (clusters) are located in one of 14 preselected French school districts and must have only one secondary school which enrols at least 2/3 of inhabitants aged 11-14 years. A randomisation stratified by school district and deprivation index allocated 90 municipalities into 6 groups of 15. The expected overall sample size estimate is 41 940 adolescents aged 11-14 years. The primary endpoint is the HPV VC (≥1 dose) among adolescents aged 11-14 years, at 2 months, at the municipality level (data from routine databases). Secondary endpoints include: HPV VC (≥1 dose at 6 and 12 months; and 2 doses at 2, 6 and 12 months); differences in knowledge, attitudes, behaviours, and intention among adolescents, parents and general practitioners between baseline and 2 months after intervention (self-administered questionnaires); incremental cost-effectiveness ratio. Implementation measures include dose, fidelity, adaptations, reached population and satisfaction (activity reports and self-administered questionnaires). Ethics and dissemination: This protocol was approved by the French Ethics Committee 'CPP Sud-Est VI' on 22 December 2020 (ID-RCB: 2020-A02031-38). No individual consent was required for this type of research; all participants were informed of their rights, in particular not to participate or to oppose the collection of data concerning them. Findings will be widely disseminated (conference presentations, reports, factsheets and academic publications). Trial registration number: NCT04945655.